Dry powder drug delivery system and methods

ABSTRACT

A pulmonary drug delivery system is disclosed, including a breath-powered, dry powder inhaler, and a cartridge for delivering a dry powder formulation. The inhaler and cartridge can be provided with a drug delivery formulation comprising, for example, a diketopiperazine and an active ingredient, including, small organic molecules, peptides and proteins, including, insulin and glucagon-like peptide 1 for the treatment of disease and disorders, for example, endocrine disease such as diabetes and/or obesity.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is an application under 35 U.S.C. §371 of InternationalPatent Application PCT/US2011/041303 filed on Jun. 21, 2011 which claimsthe benefit of U.S. provisional patent application No. 61/411,775, filedon Nov. 9, 2010 and U.S. Provisional Patent Application 61/357,039,filed Jun. 21, 2010, the disclosures each of which are incorporatedherein by reference in their entirety.

This application is a continuation-in-part of U.S. patent applicationSer. No. 12/717,884, filed Mar. 4, 2010 which claims the benefit of U.S.Provisional Patent Application Ser. Nos. 61/222,810 filed Jul. 2, 2009and 61/258,184 filed Nov. 4, 2009, and is a continuation-in-part of U.S.patent application Ser. No. 12/484,137, filed Jun. 12, 2009 which claimsthe benefit of U.S. Provisional Patent Application Ser. Nos. 61/157,506,filed Mar. 4, 2009, and 61/061,551, filed on Jun. 13, 2008, thedisclosures each of which are incorporated herein by reference in theirentirety.

TECHNICAL FIELD

The present disclosure relates to dry powder inhalation system includingdry powder inhalers, cartridges and pharmaceutical compositions fordelivering drug to the pulmonary tract and pulmonary circulation for thetreatment of disease or disorder.

BACKGROUND

Drug delivery systems for disease treatment which introduce activeingredients into the circulation are numerous and include oral,transdermal, inhalation, subcutaneous and intravenous administration.Drugs delivered by inhalation are typically delivered using positivepressure relative to atmospheric pressure in air with propellants. Suchdrug delivery systems deliver drugs as aerosols, nebulized or vaporized.More recently, drug delivery to lung tissue has been achieved with drypowder inhalers. Dry powder inhalers can be breath activated orbreath-powered and can deliver drugs by converting drug particles in acarrier into a fine dry powder which is entrained into an air flow andinhaled by the patient. Drugs delivered with the use of a dry powderinhaler are no longer only intended to treat pulmonary disease, but canalso be absorbed into the systemic circulation so they can be used totreat many conditions, including, but not limited to diabetes andobesity.

Dry powder inhalers, used to deliver medicaments to the lungs, contain adose system of a powder formulation usually either in bulk supply orquantified into individual doses stored in unit dose compartments, likehard gelatin capsules or blister packs. Bulk containers are equippedwith a measuring system operated by the patient in order to isolate asingle dose from the powder immediately before inhalation. Dosingreproducibility requires that the drug formulation is uniform and thatthe dose can be delivered to the patient with consistent andreproducible results. Therefore, the dosing system ideally operates tocompletely discharge all of the formulation effectively during aninspiratory maneuver when the patient is taking his/her dose. However,complete discharge is not generally required as long as reproducibledosing can be achieved. Flow properties of the powder formulation, andlong term physical and mechanical stability in this respect, are morecritical for bulk containers than they are for single unit dosecompartments. Good moisture protection can be achieved more easily forunit dose compartments such as blisters. However, materials used tomanufacture blisters allow air into the drug compartment andsubsequently formulations can lose viability with long storage.Additionally, dry powder inhalers which use blisters to deliver amedicament by inhalation can suffer with inconsistency of dose deliveryto the lungs due to variations in the air conduit architecture resultingfrom puncturing films or peeling films of the blisters.

Dry powder inhalers in the art can generate drug particles or suitableinhalation plumes during an inspiratory maneuver by deagglomerating thepowder formulation within a cartridge or capsule. The amount of finepowder discharged from the inhaler's mouthpiece during inhalation islargely dependent on, for example, interparticulate forces in the powderformulation and efficiency of the inhaler to separate those particles sothat they are suitable for inhalation. The benefits of delivering drugsvia the pulmonary circulation are numerous and can include rapid entryinto the arterial circulation, avoidance of drug degradation by livermetabolism, ease of use, i.e., lack of discomfort of administration byother routes of administration.

Dry powder inhaler products developed for pulmonary delivery have metwith limited success to date, due to lack of practicality and/or cost ofmanufacture. Some of the persistent problems observed with prior artinhalers, include lack of ruggedness of device, inconsistency in dosing,inconvenience of the equipment, poor deagglomeration, problems withdelivery in light of divorce from propellant use, and/or lack of patientcompliance. Therefore, the inventors have identified the need to designand manufacture an inhaler with consistent powder delivery properties,easy to use without discomfort, and discrete inhaler configurationswhich would allow for better patient compliance.

SUMMARY

Described herein generally are dry powder inhalation systems forpulmonary delivery, wherein the systems include dry powder inhalers andcontainers including cartridges for dry powder inhalers for rapid andeffective delivery of dry powder formulations to the pulmonary tract.The dry powder formulations of the inhalation systems comprise activeagents for the treatment of one or more disease, including, local orsystemic diseases or disorders, including, but not limited to diabetes,obesity, pain, headaches such as migraines, central or peripheralnervous system and immune disorders and the like, as well as fordelivery of a vaccine formulation. The dry powder inhalers can bebreath-powered, compact, reusable or disposable systems, which can havevarious shapes and sizes, and comprise a system of airflow conduitpathways for the effective and rapid delivery of dry powder medicaments.In one embodiment, the inhaler can be a unit dose, reusable ordisposable inhaler that can be used with or without a cartridge. By usewithout a cartridge we refer to systems in which cartridge-likestructures are provided that are integral to the inhaler and the inhaleris for a single use and disposable. Alternatively, in some embodiments,the systems comprise a cartridge which is provided separately andinstalled in the inhaler for use by, for example, the user. In thisembodiment, the inhaler can be a reusable inhaler and a new cartridge isinstalled in the inhaler at every use. In another embodiment, theinhaler can be a multidose inhaler, disposable or reusable, that can beused with single unit dose cartridges installed in the inhaler orcartridge-like structures built-in or structurally configured as part ofthe inhaler.

In further embodiments, the dry powder inhalation system comprises a drypowder inhalation device or inhaler with or without a cartridge, and apharmaceutical formulation comprising an active ingredient for pulmonarydelivery. In some embodiments, powder delivery is to the deep lung,including, to the alveolar region, and in some of these embodiments, theactive agents is absorbed into the pulmonary circulation for systemicdelivery. The system can also comprise a dry powder inhaler with orwithout a unit dose cartridge, and a drug delivery formulationcomprising, for example, a diketopiperazine and an active ingredientsuch as small molecules, peptides, polypeptides and proteins, includinginsulin and glucagon-like peptide 1.

In one embodiment, the dry powder inhaler comprises a housing, amoveable member, and a mouthpiece, wherein the moveable member isoperably configured to move a container from a powder containmentposition to a dosing position. In this and other embodiments, themoveable member can be a sled, a slide tray or a carriage which ismoveable by various mechanisms.

In another embodiment, the dry powder inhaler comprises a housing and amouthpiece, structurally configured to have an open position, a closedposition and a mechanism operably configured to receive, hold, andreconfigure a cartridge from a containment position to a dispensing,dosing or dose delivery position upon movement of the inhaler from theopen position to the closed position. In versions of this embodiment,the mechanism can also reconfigure a cartridge installed in the inhalerfrom the dosing position to an alternate position after use when theinhaler is opened to unload a used cartridge, thereby indicating to auser that the cartridge has been spent. In one embodiment, the mechanismcan reconfigure a cartridge to a disposable or discarding configurationafter use. In such embodiments, the housing is structurally configuredto be moveably attached to the mouthpiece by various mechanismsincluding, a hinge. The mechanism configured to receive and reconfigurea cartridge installed in the inhaler from a containment position to thedosing position can be designed to operate manually or automaticallyupon movement of the inhaler components, for example, by closing thedevice from an open configuration. In one embodiment, the mechanism forreconfiguring a cartridge comprises a slide tray or sled attached to themouthpiece and movably attached to the housing. In another embodiment,the mechanism is mounted or adapted to the inhaler and comprises ageared mechanism integrally mounted within, for example, a hinge of theinhaler device. In yet another embodiment, the mechanism operablyconfigured to receive and reconfigure the cartridge from a containmentposition to a dosing position comprises a cam that can reconfigure thecartridge upon rotation of, for example, the housing or the mouthpiece.

In an alternate embodiment, the dry powder inhaler can be made as asingle use, unit dose disposable inhaler, which can be provided with acontainer configured to hold a powder medicament and the container ismoveable from a containment configuration to a dosing configuration by auser, wherein the inhaler can have a first and a second configuration inwhich the first configuration is a containment configuration and thesecond configuration is a dosing of dispensing configuration. In thisembodiment, the inhaler can be provided with or without a mechanism forreconfiguring the powder container. According to aspects of the latterembodiment, the container can be reconfigured directly by the user. Insome aspects of this embodiment, the inhaler and container can bemanufactured as a two piece inhalation system wherein the powdermedicament is provided to the container prior to assembling the devicein a containment configuration. In this embodiment, the container isattached to the inhaler body and is moveable from the containmentconfiguration to a dosing configuration, for example, by slidingrelative to the top portion of the inhaler comprising a mouthpiece.

In yet another embodiment, an inhaler comprising a container mountingarea configured to receive a container, and a mouthpiece having at leasttwo inlet apertures and at least one exit aperture; wherein one inletaperture of the at least two inlet apertures is in fluid communicationwith the container area, and one of the at least two inlet apertures isin fluid communication with the at least one exit aperture via a flowpath configured to bypass the container area.

In one embodiment, the inhaler has opposing ends such as a proximal endfor contacting a user's lips or mouth and a distal end, and comprises amouthpiece and a medicament container; wherein the mouthpiece comprisesa top surface and a bottom or undersurface. The mouthpiece undersurfacehas a first area configured relatively flat to maintain a container in asealed or containment configuration, and a second area adjacent to thefirst area which is raised relative to the first area. In thisembodiment, the container is movable from the containment configurationto the dosing configuration and vice versa, and in the dosingconfiguration, the second raised area of the mouthpiece undersurface andthe container form or define an air inlet passageway to allow ambientair to enter the internal volume of the container or expose the interiorof the container to ambient air. In one embodiment, the mouthpiece canhave a plurality of openings, for example, an inlet port, an outlet portand at least one port for communicating with a medicament container in adispensing or dosing position, and can be configured to have integrallyattached panels extending from the bottom surface sides of the inhalerand having flanges protruding towards the center of the inhalermouthpiece, which serve as tracks and support for the container on themouthpiece so that the container can move along the tracks from thecontainment position to a dispensing or dosing position and back tocontainment if desired. In one embodiment, the medicament container isconfigured with wing-like projections or winglets extending from its topborder to adapt to the flanges on the mouthpiece panels. In oneembodiment, the medicament container can be moved manually by a userfrom containment position to a dosing position and back to thecontainment position after dosing, or by way of a sled, a slide tray, ora carriage.

In another embodiment, a single use, unit dose, disposable inhaler canbe constructed to have a sled incorporated and operably configured tothe mouthpiece. In this embodiment, a bridge on the sled can abut orrest on an area of the medicament container to move the container alongthe mouthpiece panel tracks from the containment position to thedispensing or dosing position. In this embodiment, the sled can beoperated manually to move the container on the mouthpiece tracks.

In one embodiment, the dry powder inhaler comprises one or more airinlets and one or more air outlets. When the inhaler is closed, at leastone air inlet can permit flow to enter the inhaler and at least one airinlet allows flow to enter a cartridge compartment or the interior ofthe cartridge or container adapted for inhalation. In one embodiment,the inhaler has an opening structurally configured to communicate withthe cartridge placement area and with a cartridge inlet port when thecartridge container is in a dosing position. Flow entering the cartridgeinterior can exit the cartridge through an exit or dispensing port orports; or flow entering the container of an inhaler can exit through atleast one of the dispensing apertures. In this embodiment, the cartridgeinlet port or ports is/are structurally configured so that all, or aportion of the air flow entering the interior of the cartridge isdirected at the exit or dispensing port or ports.

The medicament container is structurally configured to have twoopposing, relatively curvilinear sides which can direct airflow. In thisembodiment, flow entering the air inlet during an inhalation cancirculate within the interior of the container about an axis relativelyperpendicular to the axis of the dispensing ports, and thereby, the flowcan lift, tumble and effectively fluidize a powder medicament containedin the cartridge. In this and other embodiments, fluidized powder in theair conduit can be further deagglomerated into finer powder particles bya change in direction or velocity, i.e., acceleration or deceleration ofthe particles in the flow pathway. In certain embodiments, the change inacceleration or deceleration can be accomplished by changing the angleand geometries of, for example, the dispensing port or ports, themouthpiece conduit and/or its interfaces. In the inhalers describedherewith, the mechanism of fluidization and acceleration of particles asthey travel through the inhaler are methods by which deagglomeration anddelivery of a dry powder formulation is effectuated.

In particular embodiments, a method for deagglomerating and dispersing adry powder formulation comprises one or more steps such as tumblingwithin a primary container region started and enhanced by flow enteringthe container; a rapid acceleration of powder in the flow through thedispensing ports leaving the container; further accelerating the powderinduced by a change in direction or velocity as the powder exits thedispensing port; shearing of powder particles caught within a flowgradient, wherein the flow on the top of the particle is faster thanflow on bottom of the particle; deceleration of flow due to expansion ofcross-sectional area within the mouthpiece air conduit; expansion of airtrapped within a particle due to the particle moving from a higherpressure region to a lower pressure region, or collisions betweenparticles and flow conduit walls at any point in the flow passageways.

In another embodiment, a dry powder inhaler comprises a mouthpiece; asled, slide tray, or a carriage; a housing, a hinge, and a gearmechanism configured to effectuate movement of the sled or slide tray;wherein the mouthpiece and the housing are moveably attached by thehinge.

Cartridges for use with the dry powder inhaler can be manufactured tocontain any dry powder medicament for inhalation. In one embodiment, thecartridge is structurally configured to be adaptable to a particular drypowder inhaler and can be made of any size and shape, depending on thesize and shape of the inhaler to be used with, for example, if theinhaler has a mechanism which allows for translational movement or forrotational movement. In one embodiment, the cartridge can be configuredwith a securing mechanism, for example, having a beveled edge on thecartridge top corresponding to a matching beveled edge in an inhaler sothat the cartridge is secured in use. In one embodiment, the cartridgecomprises a container and a lid or cover, wherein the container can beadapted to a surface of the lid and can be movable relative to the lidor the lid can be movable on the container and can attain variousconfigurations depending on its position, for example, a containmentconfiguration, a dosing configuration or after use configuration.Alternatively the lid can be removable.

An exemplary embodiment can comprise an enclosure to hold medicamentconfigured having at least one inlet aperture to allow flow into theenclosure; at least one dispensing aperture to allow flow out of theenclosure; the inlet aperture configured to direct at least a portion ofthe flow at the dispensing aperture or at the particles approaching thedispensing aperture within the enclosure in response to a pressuregradient. The dispensing aperture or apertures and the intake gasaperture each independently can have a shape such as oblong,rectangular, circular, triangular, square and oval-shaped and can be inclose proximity to one another. During inhalation, a cartridge adaptedto the inhaler in a dosing position allows airflow to enter theenclosure and mix with the powder to fluidize the medicament. Thefluidized medicament moves within the enclosure such that medicamentgradually exits the enclosure through the dispensing aperture, whereinthe fluidized medicament exiting the dispensing aperture is sheared anddiluted by a secondary flow not originating from within the enclosure.In one embodiment, the flow of air in the internal volume rotates in acircular manner so as to lift a powder medicament in the container orenclosure and recirculate the entrained powder particles or powder massin the internal volume of the container promoting the flow to tumbleprior to the particles exiting dispensing ports of the container or oneor more of the inhaler inlet ports or air outlet or dispensingapertures, and wherein the recirculating flow, can cause tumbling, ornon-vortical flow of air in the internal volume acts to deagglomeratethe medicament. In one embodiment, the axis of rotation is mostlyperpendicular to gravity. In another embodiment the axis of rotation ismostly parallel to gravity. The secondary flow not originating fromwithin the enclosure further acts to de-agglomerate the medicament. Inthis embodiment, the pressure differential is created by the user'sinspiration. A cartridge for a dry powder inhaler, comprising: anenclosure configured to hold a medicament; at least one inlet port toallow flow into the enclosure, and at least one dispensing port to allowflow out of the enclosure; the at least one inlet port is configured todirect at least a portion of the flow entering the at least one inletport at the at least one dispensing port within the enclosure inresponse to a pressure differential.

A unit dose cartridge for an inhaler comprising: a substantially flatcartridge top, arrow-like in configuration, having one or more inletapertures, one or more dispensing apertures, and two side panelsextending downwardly and each of the two side panels having a track; anda container moveably engaged to the track of the side panels of thecartridge top, and comprising a chamber configured to have a relativelycup-like shape with two relatively flat and parallel sides and arelatively rounded bottom, and interior surface defining an internalvolume; the container configurable to attain a containment position anda dosing position with the cartridge top; wherein in use with a drypowder inhaler during an inhalation a flow entering the internal volumediverges as it enters the internal volume with a portion of the flowexiting through the one or more dispensing apertures and a portion ofthe flow rotating inside the internal volume and lifting a powder in theinternal volume before exiting through the dispensing apertures.

In one embodiment, an inhalation system for pulmonary drug delivery isprovided, comprising: a dry powder inhaler comprising a housing and amouthpiece having an inlet and an outlet port, an air conduit betweenthe inlet and the outlet, and an opening structurally configured toreceive a cartridge; a cartridge mounting mechanism such as a sled; acartridge configured to be adapted to the dry powder inhaler andcontaining a dry powder medicament for inhalation; wherein the cartridgecomprises a container and a lid having one or more inlet ports or one ormore dispensing ports; the dry powder inhaler system in use has apredetermined airflow balance distribution through the cartridgerelative to total flow delivered to the patient.

In embodiments disclosed herewith, the dry powder inhaler systemcomprises a predetermined mass flow balance within the inhaler. Forexample, a flow balance of approximately 20% to 70% of the total flowexiting the inhaler and into the patient is delivered by the dispensingports or passed through the cartridge, whereas approximately 30% to 80%is generated from other conduits of the inhaler. Moreover, bypass flowor flow not entering and exiting the cartridge can recombine with theflow exiting the dispensing port of the cartridge within the inhaler todilute, accelerate and ultimately deagglomerate the fluidized powderprior to exiting the mouthpiece.

In the embodiments described herein, the dry powder inhaler is providedwith relatively rigid air conduits or plumbing system and high flowresistance levels to maximize deagglomeration of powder medicament andfacilitate delivery. Inhalation systems disclosed herein compriseconduits which exhibit resistance to flow in use maintaining low flowrates which minimize high inertial forces on powder particles dischargedfrom the inhaler, preventing throat deposition or impaction of thepowder particles in the upper respiratory tract, and thereby, maximizingpowder particle deposition in the lungs. Accordingly, the presentinhalation systems provide effective and consistent powder medicamentdischarge from the inhalers after repeated use since the inhalers areprovided with air conduit geometries which remain the constant andcannot be altered. In some embodiments, the dry powder medicament isdispensed with consistency from an inhaler in less than about 3 seconds,or generally less than one second. In some embodiments, the inhalersystem can have a high resistance value of, for example, approximately0.065 to about 0.200 (√kPa)/liter per minute. Therefore, in theinhalation systems, peak inhalation pressures drop offs between 2 and 20kPa produce resultant peak flow rates of about between 7 and 70 litersper minute. These flow rates result in greater than 75% of the cartridgecontents dispensed in fill masses between 1 and 30 mg or greater. Insome embodiments, these performance characteristics are achieved by endusers within a single inhalation maneuver to produce cartridge dispensepercentages greater than 90%. In certain embodiments, the inhaler andcartridge system are configured to provide a single dose by dischargingpowder from the inhaler as a continuous flow of powder delivered to apatient.

In one embodiment, a method for effectively deagglomerating a dry powderformulation during an inhalation in a dry powder inhaler is provided.The method can comprise the steps of providing a dry powder inhalercomprising a container having an air inlet, dispensing portscommunicating with a mouthpiece air conduit and containing anddelivering a formulation to a subject in need of the formulation;generating an airflow in the inhaler by the subject's inspiration sothat about 20 to about 70% of the airflow entering the inhaler entersand exits the container; allowing the airflow to enter the containerinlet, circulate and tumble the formulation in an axis perpendicular tothe dispensing ports to fluidize the formulation so as to yield afluidized formulation; accelerating metered amounts of fluidizedformulation through the dispensing ports and in the air conduit, anddecelerating the airflow containing fluidized formulation in themouthpiece air conduit of the inhaler prior to reaching the subject. Insome specific embodiments, 20% to 60% of the total flow through theinhaler goes through the cartridge during dose delivery.

In another embodiment, a method for deagglomerating and dispersing a drypowder formulation for inhalation is provided, comprising the steps of:generating an airflow in a dry powder inhaler comprising a mouthpieceand a container having at least one inlet port and at least onedispensing port and containing a dry powder formulation; the containerforming an air passage between at least one inlet port and at least onedispensing port and the inlet port directs a portion of the airflowentering the container to at least one dispensing port; allowing airflowto tumble powder within the container in a substantially perpendicularaxis to the at least one dispensing port so as to lift and mix the drypowder medicament in the container to form an airflow medicamentmixture; and accelerating the airflow exiting the container through atleast one dispensing port. In one embodiment, the inhaler mouthpiece isconfigured to have a gradual expanding cross-section to decelerate flowand minimize powder deposition inside the inhaler and promote maximaldelivery of powder to the patient. In one embodiment, for example, thecross-sectional area of the oral placement region of an inhaler can befrom about 0.05 cm² to about 0.25 cm² over an approximate length ofabout 3 cm. These dimensions depend on the type of powder used with theinhaler and the dimensions of the inhaler itself.

In one embodiment, a cartridge for a dry powder inhaler is provided,comprising: a cartridge top and a container defining an internal volume;wherein the cartridge top has an undersurface that extends over thecontainer; the undersurface configured to engage the container, andcomprising an area to contain the internal volume and an area to exposethe internal volume to ambient air.

In an alternate embodiment, a method for the delivery of particlesthrough a dry powder delivery device is provided, comprising: insertinginto the delivery device a cartridge for the containment and dispensingof particles comprising an enclosure enclosing the particles, adispensing aperture and an intake gas aperture; wherein the enclosure,the dispensing aperture, and the intake gas aperture are oriented suchthat when an intake gas enters the intake gas aperture, the particlesare deagglomerated, by at least one mode of deagglomeration as describedabove to separate the particles, and the particles along with a portionof intake gas are dispensed through the dispensing aperture;concurrently forcing a gas through a delivery conduit in communicationwith the dispensing aperture thereby causing the intake gas to enter theintake gas aperture, de-agglomerate the particles, and dispense theparticles along with a portion of intake gas through the dispensingaperture; and, delivering the particles through a delivery conduit ofthe device, for example, in an inhaler mouthpiece. In embodimentdescribed herein, to effectuate powder deagglomeration, the dry powderinhaler can be structurally configured and provided with one or morezones of powder deagglomeration, wherein the zones of deagglomerationduring an inhalation maneuver can facilitate tumbling of a powder by airflow entering the inhaler, acceleration of the air flow containing apowder, deceleration of the flow containing a powder, shearing of apowder particles, expansion of air trapped in the powder particles,and/or combinations thereof.

In another embodiment, the inhalation system comprises a breath-powereddry powder inhaler, a cartridge containing a medicament, wherein themedicament can comprise, for example, a drug formulation for pulmonarydelivery such as a composition comprising a diketopiperazine and anactive agent. In some embodiments, the active agent comprises peptidesand proteins, such as insulin, glucagon-like peptide 1, oxyntomodulin,peptide YY, exendin, parathyroid hormone, analogs thereof, smallmolecules, vaccines and the like. The inhalation system can be used, forexample, in methods for treating conditions requiring localized orsystemic delivery of a medicament, for example, in methods for treatingdiabetes, pre-diabetes conditions, respiratory track infection,osteoporosis, pulmonary disease, pain including headaches including,migraines, obesity, central and peripheral nervous system conditions anddisorders and prophalactic use such as vaccinations. In one embodiment,the inhalation system comprises a kit comprising at least one of each ofthe components of the inhalation system for treating the disease ordisorder.

In one embodiment, there is provided a method for the effective deliveryof a formulation to the blood stream of a subject, comprising aninhalation system comprising an inhaler including a cartridge containinga formulation comprising a diketopiperazine, wherein the inhalationsystem delivers a powder plume comprising diketopiperazinemicroparticles having a volumetric median geometric diameter (VMGD)ranging from about 2.5 μm to 10 μm. In an example embodiment, the VMGDof the microparticles can range from about 2 μm to 8 μm. In an exampleembodiment, the VMGD of the powder particles can be from 4 μm to about 7μm in a single inhalation of the formulation of fill mass rangingbetween 3.5 mg and 10 mg of powder. In this and other embodiments, theinhalation system delivers greater than 90% of the dry powderformulation from the cartridge.

In another embodiment, there is provided a dry powder inhalercomprising: a) a mouthpiece configured to deliver a dry powder to asubject by oral inhalation; b) a container housing, and c) rigid airconduits extending between the container housing and the mouthpiece andconfigured to communicate with ambient air; wherein the dry powderinhaler is configured to emit greater than 75% of a dry powder as powderparticles from a container oriented in the container housing in a singleinhalation and the powder particles emitted have a volumetric mediangeometric diameter (VMGD) of less than about 5 microns, when a userinhales through the mouthpiece to generate a peak inspiratory pressureof about 2 kPa within two seconds and an area under the curve (AUC)within 1 second for a pressure versus time curve of at least about 1.0,1.1 or 1.2 kPa*sec. In another embodiment, the AUC within 1 second for apressure versus time curve is between about 1.0 and about 15 kPa*sec.

In some embodiments, there is also provided a method of delivering adose of a dry powder medication using a high resistance dry powderinhaler comprising, providing a high resistance dry powder inhalercontaining a dose of a dry powder medicament and inhaling from theinhaler with sufficient force (or effort) to reach a peak inspiratorypressure of at least 2 kPa within 2 seconds; and generating an areaunder the curve in the first second (AUC_(0-1sec)) of a inspiratorypressure versus time curve of at least about 1.0, 1.1 or 1.2 kPa*sec;wherein greater than 75% of the dry powder dose is discharged or emittedfrom the inhaler as powder particles. In some embodiments the VMGD ofthe emitted particles is less than about 5 microns.

In another embodiment, a method of delivering an adequatelyde-agglomerated dose of a dry powder medication using a high resistancedry powder inhaler comprising, providing a high resistance dry powderinhaler containing a dose of a dry powder medicament; inhaling from theinhaler with sufficient force to reach a peak inspiratory pressure of atleast 2 kPa within 2 seconds; and generating an area under the curve inthe first second (AUC_(0-1sec)) of a inspiratory pressure-time curve ofat least about 1.0, 1.1, or 1.2 kPa*second; wherein VMGD (×50) of theemitted powder is less than about 5 um. In an alternative embodiment,the dry powder is composed of microparticles with a median particle sizeand the VMGD (×50) of the emitted powder particles is not greater than1.33 times the median particle size when the inhaler is used optimally,for example, at about 6 kPa.

In another embodiment, described is a use of a high resistance drypowder inhaler for the delivery of a dry powder wherein the dry powderinhaler having an airflow resistance value ranging from about 0.065(√kPa)/liter per minute to about 0.200 (√kPa)/liter per minute, andcontaining the dose of the dry powder, wherein sufficient force isapplied to reach a peak inspiratory pressure of at least 2 kPa within 2seconds; and wherein an area under the curve in the first second(AUC_(0-1sec)) of a inspiratory pressure versus time curve of at leastabout 1.0, 1.1 or 1.2 kPa*sec is generated; and wherein greater than 75%of the dose of the dry powder is discharged or emitted from the inhaleras powder particles.

In some embodiments the inhalation systems described herein are used totreat patients in need of treatment of a disease or disorder describedherein using a medicament as described.

In still another embodiment, a high resistance dry powder inhaler foruse to deliver a dry powder medicament to a patient is described,characterized in that the dry powder inhaler is provided having anairflow resistance value ranging from about 0.065 (√kPa)/liter perminute to about 0.200 (√kPa)/liter per minute, and containing a dose ofthe dry powder medicament, wherein in use sufficient force is applied toreach a peak inspiratory pressure of at least 2 kPa within 2 seconds;and an area under the curve is generated in the first second(AUC_(0-1sec)) of an inspiratory pressure versus time curve of at leastabout 1.0, 1.1 or 1.2 kPa*sec; and wherein greater than 75% of the doseof the dry powder is discharged or emitted from the inhaler as powderparticles.

In another embodiment, an inhalation system is provided comprising aninhaler, a cartridge containing a dry powder formulation for delivery tothe systemic circulation comprising diketopiperazine microparticles;wherein the diketopiperazine microparticles deliver a plasma level(exposure) of diketopiperazine having an AUC_(0-2 hr) between 1,300ng*min/mL and 3,200 ng*min/mL per mg of diketopiperazine emitted in asingle inhalation. In another exemplary embodiment, an inhalation systemis provided comprising an inhaler, a cartridge containing a dry powderformulation for delivery to the systemic circulation comprisingdiketopiperazine microparticles; wherein the diketopiperazinemicroparticles deliver a plasma level (exposure) of diketopiperazinehaving an AUC_(0-∞) greater than 2,300 ng*min/mL per mg of powderemitted in a single inhalation. In an aspect of such embodiments the DKPis FDKP. In this and other embodiments, the diketopiperazinemicroparticles do not cause a reduction in lung function as assessed bypulmonary function tests and measured as forced expiratory volume in onesecond (FEV1). In certain embodiments, the measured plasma exposure ofFDKP in a subject can be greater than 2,500 ng*min/mL per mg of FDKPpowder emitted in a single inhalation. In alternate embodiments, themeasured plasma exposure, AUC_(0-∞) of FDKP of a subject can be greaterthan 3,000 ng*min/mL per mg of FDKP powder emitted in a singleinhalation. In yet another embodiment, the measured plasma exposure ofFDKP AUC_(0-∞) in a subject can be less than or about 5,500 ng*min/mLper mg of FDKP emitted in a single inhalation of a dry powdercomposition comprising FDKP. In some embodiments, the stated level ofexposure represents an individual exposure. In alternate embodiments,the stated level of exposure represents a mean exposure. Active agentquantities, including contents and exposures may be expressalternatively in units of activity or mass.

In these and other embodiments, the microparticles can further comprisean active ingredient. In particular embodiments, the active ingredientis insulin. In another exemplary embodiment, an inhalation system isprovided comprising an inhaler, a cartridge containing a dry powderformulation for delivery to the systemic circulation comprisingdiketopiperazine microparticles containing insulin; wherein thediketopiperazine microparticles deliver a plasma level (exposure) ofinsulin with an AUC_(0-2 hr) greater than 160 μU*min/mL per units ofinsulin in the powder formulation emitted in a single inhalation. In anaspect of this embodiment, the inhalation system is configured todeliver and attain an insulin plasma level or exposure wherein themeasured insulin AUC_(0-2 hr) ranges from about 100 to 1,000 μU*min/mLper units of insulin in the powder formulation emitted in a singleinhalation. In some embodiments, the stated level of exposure representsan individual exposure. In alternate embodiments, the stated level ofexposure represents a mean exposure.

In another exemplary embodiment, an inhalation system is providedcomprising an inhaler, a cartridge containing a dry powder formulationfor delivery to the systemic circulation comprising diketopiperazinemicroparticles comprising insulin; wherein the diketopiperazinemicroparticles deliver a plasma level (exposure) of insulin with anAUC_(0-4 hr) greater than 100 μU*min/mL per U of insulin filled emittedin a single inhalation. In an aspect of this embodiment, the inhalationsystem is configured to deliver to a patient a formulation of insulinand fumaryl diketopiperazine which attains a plasma exposure of insulinhaving measured AUC_(0-4 hr) in the range of 100 to 250 μU*min/mL per Uof insulin filled dose, emitted in a single inhalation. In aspects ofthese embodiments, the AUC_(0-4 hr) can be greater than 110, 125, 150 or175 μU*min/mL per U of insulin filled, emitted in a single inhalation.In this and other embodiments, the insulin content of the formulationcomprises from about 10 to about 20% (w/w) of the formulation

In still another exemplary embodiment, an inhalation system is providedcomprising an inhaler, a cartridge containing a dry powder formulationfor delivery to the systemic circulation comprising diketopiperazinemicroparticles containing insulin; wherein the diketopiperazinemicroparticles deliver a plasma level of insulin with a C_(max) over 10μU/mL per mg of powder emitted in a single inhalation, within 30 minutesof administration. In an aspect of this embodiment, the insulinformulation administered generates a C_(max) ranging from about 10 to 20μU/mL per mg of powder emitted in a single inhalation, and within 30minutes after administration. In further aspects of this embodiment,insulin C_(max) can be attained within 25, 20, or 15 minutes ofadministration. In alternatives of these C_(max) embodiments, theC_(max) attained after pulmonary inhalation of the formulation isgreater than 3 μU/mL per U of insulin filled into a cartridge, or in therange of 3 U to 6 U, or 4 U to 6 μU/mL per U of insulin in a cartridgedose.

In another embodiment, an inhalation system, comprising: a dry powderinhaler; and a dry powder formulation comprising a plurality of powderparticles of a diketopiperazine is provided, wherein the inhalationsystem is configured to deliver the diketopiperazine to the pulmonarycirculation of a subject, and the diketopiperazine can be measured inthe subject's plasma having a mean exposure or AUC_(0-∞) greater than2,300 ng*min/mL per mg of diketopiperazine content in the dry powderformulation administered in a single inhalation. In one embodiment, theinhalation system further comprises a cartridge configured to adapt to abreath powered dry powder inhaler. In this and other embodiments, thediketopiperazine in the formulation is3,6-bis(N-fumaryl-4-aminobutyl)-2,5-diketopiperazine (FDKP).

In embodiments wherein FDKP is used in the formulation, the system candeliver the FDKP into the systemic circulation at a T_(max) of less than1 hour. In some embodiments, the T_(max) for FDKP can be less than 15 or30 minutes after administration of the FDKP in a single inhalation. Inthis an other embodiments, the AUC is measured from 0 to 2 hours, 0 to 4hrs or 0 to ∞.

In another embodiment, an inhalation system, comprising: abreath-powered dry powder inhaler, and a dry powder formulationcomprising a plurality of diketopiperazine particles is provided;wherein the inhalation system is operably configured to emit a powderplume comprising the diketopiperazine microparticles having a volumetricmedian geometric diameter ranging from 2 μm to 8 μm and a geometricstandard deviation of less than 4 μm.

In yet another embodiment, an inhalation system for pulmonary deliveryof a drug, comprising: a breath-powered dry powder inhaler, and a drypowder formulation comprising a plurality of diketopiperazine particlesis provided; wherein the inhalation system is operably configured toemit more than 90% of the powder particles that dissolve and areabsorbed into the blood in less than 30 minutes or less than 25 minutesyield a peak concentration of the diketopiperazine after a singleinhalation of the dry powder formulation. In some embodiments, thesystem emits more than 95% of the powder particles in a singleinhalation, which particles are absorbed into the circulation.

In one embodiment, an inhalation system, comprising: a dry powderinhaler; and a dry powder formulation comprising a plurality of drypowder particles comprising insulin is provided; wherein the inhalationsystem is configured to deliver the insulin to the pulmonary circulationof a subject, and the insulin can be measured in a subject's plasma atan exposure having a mean AUC_(0-2 hr) greater than 160 uU*min/mL perunit of insulin emitted in the dry powder formulation administered in asingle inhalation.

In one embodiment, the inhalation system, the dry powder formulation isadministered to a subject by oral inhalation and the formulationcomprises powder particles of insulin which can deliver the insulin tothe subject systemic circulation, wherein a Cmax for insulin is measuredin less than 30 minutes after administration to a patient in a singleinhalation.

In an embodiment, there is provided an inhalation system, comprising: abreath-powered dry powder inhaler, and a powder formulation comprising aplurality of diketopiperazine particles; wherein the inhalation systemis operably configured to emit a powder plume comprising thediketopiperazine microparticles having a volumetric median geometricdiameter ranging from 2 μm to 8 μm and a geometric standard deviation ofless than 4 μm.

In yet another embodiment, an inhalation system for pulmonary deliveryof a drug is provided, comprising: a breath-powered dry powder inhaler,and a powder formulation comprising a plurality of diketopiperazineparticles; wherein the inhalation system is operably configured to emitpowder particles that are absorbed into the blood to yield a peakconcentration of the drug in less than or equal to 30, 25, 20, or 15minutes.

In one embodiment, a dry powder inhaler comprising a mouthpiececonfigured to deliver a dry powder to a subject by oral inhalation, acontainer configured to hold a dry powder, and air conduits extendingbetween the container and the mouthpiece and configured to communicatewith ambient air, wherein the dry powder inhaler is configured to emitgreater than 75% of the dry powder as powder particles in a singleinhalation and the powder particles emitted have a volumetric mediangeometric diameter of less than 5 microns, when a user inhales throughthe mouthpiece to generate a peak inspiratory pressure of about 2 kPawithin two seconds, and an AUC_(0-1sec) a inspiratory pressure versustime curve of at least about 1.0, of 1.1 or 1.2 kPa*sec; wherein greaterthan 75% of the dry powder dose is discharged or emitted from theinhaler as powder particles.

In yet another embodiment, a method of delivering a dose of a dry powdermedication to a subject is disclosed using a high resistance dry powderinhaler comprising the steps of providing a dry powder inhaler having aresistance value to airflow ranging from about 0.065 (√kPa)/liter perminute to about 0.200 (√kPa)/liter per minute and containing a dose of adry powder medicament; inhaling from the inhaler with sufficient forceto reach a peak inspiratory pressure of at least 2 kPa within 2 seconds;and generating an AUC_(0-1sec) of a inspiratory pressure versus timecurve of at least about 1.0, 1.1 or 1.2 kPa*sec; wherein greater than75% of the dry powder dose is discharged or emitted from the inhaler aspowder particles.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts an example embodiment of the inhaler used in theinhalation system, showing an isometric view of the inhaler in a closedconfiguration.

FIGS. 2, 3, 4, 5, and 6 depict side, top, bottom, proximal and distalviews, respectively, of the inhaler of FIG. 1.

FIG. 7 depicts a perspective view of an embodiment of the inhalationsystem comprising the inhaler of in FIG. 1 in an open configurationshowing a corresponding cartridge and a mouthpiece covering.

FIG. 8 depicts an isometric view of the inhaler of FIG. 6 in an openconfiguration with a cartridge installed in the holder in cross-sectionthrough the mid-longitudinal axis with a cartridge installed in thecartridge holder and in a containment configuration, and the closedconfiguration of the inhaler and in dosing configuration of thecartridge FIG. 9.

FIG. 10 illustrates a perspective view of an alternate embodiment of adry powder inhalation system, the inhaler shown in an openedconfiguration, illustrating the type and orientation of a correspondingcartridge that can be installed in the inhaler.

FIG. 11 depicts an isometric view of the dry powder inhaler of FIG. 10in an open configuration.

FIG. 12 illustrates an exploded view of the inhaler embodiment of FIG.48 showing the inhaler component parts.

FIG. 13 illustrates a perspective view of the inhaler in FIG. 10 in theopen configuration and showing a cartridge installed in the inhaler.

FIG. 14 illustrates a mid-longitudinal section of the inhaler depictedin FIG. 12 showing the cartridge container in the containmentconfiguration and in contact with the sled and the gear mechanism incontact with the sled.

FIG. 15 illustrates a perspective view of the inhaler in FIG. 10 in theclosed configuration and with a cartridge in the holder.

FIG. 16 illustrates a mid-longitudinal section of the inhaler depictedin FIG. 53 showing the cartridge container in the dosing configurationand the air flow pathway established through the container.

FIG. 17 illustrates a perspective view of a cartridge embodiment for usewith the inhaler of FIG. 1 and depicting the cartridge in a containmentconfiguration.

FIG. 18 illustrates a top view of the cartridge embodiment of FIG. 17,showing the component structures of the cartridge top surface.

FIG. 19 illustrates a bottom view of the cartridge embodiment of FIG.17, showing the component structures of the cartridge undersurface.

FIG. 20 illustrates a perspective view of a cartridge embodiment of FIG.17 in mid-longitudinal cross-section and in a containment configuration.

FIG. 21 illustrates a perspective view of a cartridge embodiment of FIG.17 in a mid-longitudinal cross-section and in a dosing configuration.

FIG. 22 depicts a perspective view of an alternate embodiment of acartridge in a containment configuration.

FIG. 23 through 27 depict the cartridge embodiment shown in FIG. 22 in atop, bottom, proximal, distal and side views, respectively.

FIG. 28 depicts a perspective view of the cartridge embodiment shown inFIG. 22 in a dosing configuration.

FIGS. 29 and 30 are cross-sections through the longitudinal axis of thecartridge embodiment of FIGS. 22 and 28, respectively.

FIG. 31 is a schematic representation of the movement of flow within thepowder containment area of a dry powder inhaler as indicated by thearrows.

FIG. 32 is a schematic representation of an embodiment of a dry powderinhaler showing the flow pathways and direction of flow through theinhaler as indicated by the arrows.

FIG. 33 illustrates a graph of measurements of flow and pressurerelationship based on the Bernoulli principle for an exemplaryembodiment of the resistance to flow of an inhaler.

FIG. 34 depicts the particle size distribution obtained with a laserdiffraction apparatus using an inhaler and cartridge containing a drypowder formulation for inhalation comprising insulin and fumaryldiketopiperizine particles.

FIG. 35 depicts graphic representations of data obtained from theaverage of all tests performed for an example inhalation system (DPI 2)and MEDTONE® (MTC), showing the cumulative geometric particle sizedistribution of particles emitted from the inhalation systems fromdifferent cartridge powder contents.

FIG. 36 depict graphs of inhalation recordings with an inhalationmonitoring system and performed by a subject with an exemplaryinhalation system without (curve A) and with (curve B) a powderformulation.

FIG. 37 is a graph of the concentration of FDKP in plasma from samplestaken from the same subject as in FIG. 36 for 6 hours after inhalationof a dry powder formulation containing FDKP microparticles.

FIG. 38 is a graph of insulin concentrations over time by dose group.

FIG. 39 is a graph of FDKP concentrations over time by dose group.

FIG. 40 is a graph of glucose excursions for each individual in theStudy.

FIG. 41 is a graph of an exemplary inhalation profile of a presentdevice in use showing peak inspiratory pressure within two seconds.

FIG. 42 is a graph of exemplary inhalers showing performance criteriafor the present inhalers.

DETAILED DESCRIPTION

Disclosed herein generally are dry powder inhalers, cartridges for a drypowder inhalers and inhalation systems for delivering one or morepharmaceutical medicaments to a patient via pulmonary inhalation. In oneembodiment, an inhalation system comprises a breath-powered dry powderinhaler, and a cartridge containing a pharmaceutical formulationcomprising a pharmaceutically active substance or active ingredient anda pharmaceutically acceptable carrier. The dry powder inhaler isprovided in various shapes and sizes, and can be reusable or for singleuse, easy to use, is inexpensive to manufacture and can be produced inhigh volumes in simple steps using plastics or other acceptablematerials. In addition to complete systems, inhalers, filled cartridgesand empty cartridges constitute further embodiments disclosed herein.The present inhalation system can be designed to be used with any typeof dry powder. In one embodiment, the dry powder is a relativelycohesive powder which requires optimal deagglomeration condition. In oneembodiment, the inhalation system provides a re-useable, miniaturebreath-powered inhaler in combination with single-use cartridgescontaining pre-metered doses of a dry powder formulation.

Methods for the effective and consistent delivery of a pharmaceuticalformulation to the systemic circulation are also disclosed.

As used herein the term “a unit dose inhaler” refers to an inhaler thatis adapted to receive a single container a dry powder formulation anddelivers a single dose of a dry powder formulation by inhalation fromcontainer to a user. It should be understood that in some instancemultiple unit doses will be required to provide a user with a specifieddosage.

As used herein the term “a multiple dose inhaler” refers to an inhalerhaving a plurality of containers, each container comprising apre-metered dose of a dry powder medicament and the inhaler delivers asingle dose of a medicament powder by inhalation at any one time.

As used herein a “container” is an enclosure configured to hold orcontain a dry powder formulation, a powder containing enclosure, and canbe a structure with or without a lid. This container can be providedseparately from the inhaler or can be structurally integrated within theinhaler (e.g. non-removable). Further, the container can be filled witha dry powder. A cartridge can also include a container.

As used herein a “powder mass” is referred to an agglomeration of powderparticles or agglomerate having irregular geometries such as width,diameter, and length.

As used herein, the term “microparticle” refers to a particle with adiameter of about 0.5 to about 1000 μm, irrespective of the preciseexterior or interior structure. However four pulmonary deliverymicroparticles that are less than 10 μm are generally desired,especially those with mean particles sizes of less than about 5.8 μm indiameter.

As used herein a “rigid air conduit” refers to an air conduit that isassociated with the pathway of air through the inhalation system thatdoes not change in geometry or remains constant, for example, in areusable inhaler the air conduits remain the same after repeated use.The rigid air conduit can be associated with a mouthpiece, container,inhaler housing, container, container housing or the like.

As used herein a “unit dose” refers to a pre-metered dry powderformulation for inhalation. Alternatively, a unit dose can be a singlecontainer having multiple doses of formulation that can be delivered byinhalation as metered single amounts. A unit dose cartridge/containercontains a single dose. Alternatively it can comprise multipleindividually accessible compartments, each containing a unit dose.

As used herein, the term “about” is used to indicate that a valueincludes the standard deviation of error for the device or method beingemployed to determine the value.

The present devices can be manufactured by several methods, however, inone embodiment, the inhalers and cartridges are made, for example, byinjection molding techniques, thermoforming, using various types ofplastic materials, including, polypropylene, cyclicolephin co-polymer,nylon, polyesters such as polyethylenes, and other compatible polymersand the like. In certain embodiments, the dry powder inhaler can beassembled using top-down assembly of individual component parts. In someembodiments, the inhalers are provided in compact sizes, such as fromabout 1 inch to about 5 inches in dimension, and generally, the widthand height are less than the length of the device. In certainembodiments the inhaler is provided in various shapes including,relatively rectangular bodies, cylindrical, oval, tubular, squares,oblongs, and circular forms.

In embodiments described and exemplified herewith, the inhalation systemcomprising inhaler, cartridge or container, and a dry powderformulation, the inhalers are configured with the cartridge toeffectively fluidize, deagglomerate or aerosolize a dry powderformulation by using at least one relatively rigid flow conduit pathwayfor allowing a gas such as air to enter the inhaler. For example, theinhaler is provided with a first air/gas pathway for entering andexiting a cartridge containing the dry powder, and a second air pathwaywhich can merge with the first air flow pathway exiting the cartridge.The flow conduits, for example, can have various shapes and sizesdepending on the inhaler configuration. Examples of inhalers andcartridges that can be used in the present inhalation system aredisclosed in, for example, U.S. patent application Ser. No. 12/484,125(US 2009/0308390), Ser. No. 12/484,129 (US 2009/0308391), Ser. No.12/484,137 (US 2009/0308392), and Ser. No. 12/717,884 (US 2010/0197565)all of which are incorporated herein by reference in their entirety forall they disclose regarding inhalation systems.

In embodiments exemplified herewith, each inhaler can be used with asuitable cartridge. However, the inhalation system can perform moreefficiently when inhaler and cartridge are designed to correspond to oneanother. For example, the cartridge mounting area of an inhaler can bedesigned to house only a specific cartridge and therefore, structuralconfigurations of the openings of cartridge and inhaler match or fit oneanother, for example, as keying areas or surfaces which can aid assafety parameter for users. Examples of a corresponding inhaler andcartridge follows herewith as inhaler 302 which can be used withcartridge 170 and inhaler 900 which can be used with cartridge 150.These inhalers and cartridges have been disclosed in U.S. patentapplication Ser. Nos. 12/484,125; 12/484,129, and 12/484,137, all ofwhich are incorporated by reference herein in their entirety for allthey disclose regarding inhalers and cartridges, and where appropriate,for teachings of additional or alternative details, features, and/ortechnical background.

An embodiment of a dry powder inhaler is exemplified in FIGS. 1-9. Inthis embodiment, the dry powder inhaler has two configurations, i.e., aclosed configuration is illustrated in FIGS. 1 through 6 and 9, and anopen configuration is illustrated in FIGS. 7 and 8. The dry powderinhaler 302 in the open configuration permits installation or removal ofa cartridge containing a medicament for inhalation. FIGS. 1-6 depictinhaler 302 in a closed configuration from various views and having arelatively rectangular body comprising a housing 320, mouthpiece 330superiorly to the body and extending outwardly from the body. A portionof mouthpiece 330 tapers towards the end for contacting a user and hasan opening 335. Inhaler 302 also comprises a gear mechanism 363, and asled. Inhaler 302 can be manufactured using, for example, four parts ina top down assembly manner. Mouthpiece 330 further comprises air conduit340 configured to run along the longitudinal axis of the inhaler and hasan oral placement portion 312, air inlet 310 and air outlet 335configured to have its surface angular or beveled relative to thelongitudinal axis of the air conduit, and cartridge port opening 355which is in fluid communication with housing 320 and/or a cartridgeinstalled in housing 320 for allowing airflow to enter air conduit 340from the housing or from a cartridge installed in the inhaler in use.FIG. 1 illustrates inhaler 302 in isometric view in a closed positionhaving a more slender body 305 than inhaler 300 formed by housing 320and cover portion 308 of mouthpiece 330, which extends over and engageshousing 320 by a locking mechanism 312, for example, a protrusion. FIGS.2-6 depict side, top, bottom, proximal and distal views, respectively,of the inhaler of FIG. 1. As shown in the figures, inhaler 302 comprisesmouthpiece 330 having an oral placement section 312, an extended portionconfigured as a cover 308 that can attach to housing 320 at at least onelocation as shown in FIG. 7. Mouthpiece 330 can pivot to open from aproximal position from a user's hands in an angular direction by hingemechanism 363. In this embodiment, inhaler 302 is configured also tohave gear mechanism 363 as illustrated in FIG. 8 integrated within thehinge for opening the inhaler or mouthpiece 330 relative to housing 320.

Gear mechanism or rack 319 which is part of sled 317 and pinion 363 areconfigured with the mouthpiece as part of the hinge mechanism to engagehousing 320, which housing can also be configured to house sled 317. Inthis embodiment, sled 317 is configured as a separate part and has aportion configured as a rack which engages the gearwheel configured onthe hinge mechanism. Hinge mechanism 363 allows movement of mouthpiece330 to an open or cartridge loading configuration, and closeconfiguration or position of inhaler 302 in an angular direction. Gearmechanism 363 in inhalers 300, 302 can actuate the sled to allowconcurrent movement of sled 317 within housing 320 when the inhaler iseffectuated to open and close by movement of mouthpiece 330, which sled317 is integrally configured with rack 319 as part of gear mechanism363. In use with a cartridge, the inhaler's gear mechanism 363 canreconfigure a cartridge by movement of sled 317 during closing of theinhaler, from a cartridge containment configuration after a cartridge isinstalled on the inhaler housing or mounting area to a dosingconfiguration when the inhaler is closed. Movement of the mouthpiece 330to an open inhaler configuration after inhalation with a cartridge 170,or to a disposable configuration after a subject has effectuated dosingof a dry powder formulation. In the embodiment illustrated herein, thehinge and gear mechanism are provided at the distal end of the inhaler,however, other configurations can be provided so that the inhaler opensand closes to load or unload a cartridge as a clam-like configuration.

As shown in FIG. 1 and in use, airflow enters the inhaler through airinlet 310 and simultaneously into air conduit 340 which passes cartridge170 through air inlet 355. In one example embodiment, the internalvolume of mouthpiece 330 air conduit 340 extending from inlet port 355to outlet port 335 is greater than about 0.2 cm³. In other exampleembodiments, the internal volume is about 0.3 cm³, or about 0.3 cm³, orabout 0.4 cm³ or about 0.5 cm³. In another example embodiment, thisinternal volume of the mouthpiece is greater than 0.2 cm³ is theinternal volume of the mouthpiece 330. In an example embodiment, theinternal volume of mouthpiece ranges from 0.2 to 6.5 cm³. A powdercontained within cartridge container 175 is fluidized or entrained intothe airflow entering the cartridge through tumbling of the powdercontent. The fluidized powder then gradually exits through dispensingport 173, 127 and into the mouthpiece air conduit 340 and furtherdeagglomerated and diluted with the airflow entering at air inlet 310,prior to exiting outlet port 335.

In one embodiment, housing 320 comprises one or more component parts,for example, a top portion 316 and a bottom portion 318. The top andbottom portions are configured to adapt to one another in a tight seal,forming an enclosure which houses sled 317 and the hinge and/or gearmechanisms 363. Housing 320 is also configured to have one or moreopenings 309 to allow air flow into the interior of the housing, alocking mechanism 313, such as protrusions or snap rings to engage andsecure mouthpiece cover portion 308 in the closed position of inhaler302. Housing 320 is also configured to have a cartridge holder orcartridge mounting area 315 which is configured to correspond to thetype of cartridge to be used with the inhaler. In this embodiment, thecartridge placement area or holder is an opening in the top portion ofhousing 320 which opening also allows the cartridge bottom portion orcontainer to lie on sled 317 once a cartridge is installed in inhaler302. The housing can further comprise grasping areas 304, 307 configuredto aid a user of the inhaler to firmly or securely grip the inhaler toopen it to load or unload a cartridge. Housing 320 can further compriseflanges configured to define an air channel or conduit, for example, twoparallel flanges 303 which are also configured to direct air flow intothe inhaler air inlet 310 and into a cartridge air inlet of thecartridge air conduit positioned in the inhaler. Flanges 310 are alsoconfigured to prevent a user from obstructing inlet port 310 of inhaler302.

FIG. 7 depicts an isometric view of the inhaler of FIG. 1 in an openconfiguration with mouthpiece covering, for example, cap 342 andcartridge 170 which are configured to correspond to the cartridgemounting area and allow a cartridge to be installed in cartridge holder315 for use. In one embodiment, reconfiguration of a cartridge from acontainment position, as provided after manufacturing, can beeffectuated once the cartridge is installed in cartridge holder 315,which is configured within housing 320 and to adapt to the inhaler sothat the cartridge has the proper orientation in the inhaler and canonly be inserted or installed in only one manner or orientation. Forexample, cartridge 170 can be configured with locking mechanism 301 thatmatches a locking mechanism configured in the inhaler housing, forexample, the inhaler mounting area, or holder can comprise a bevelededge 301 which would correspond to a beveled edge 180 on the cartridgeof, for example, cartridge 170 to be installed in the inhaler. In thisembodiment, the beveled edges form the locking mechanism which preventsthe cartridge from popping out of holder 315 during movement of sled317.

In one particular embodiment illustrated in FIGS. 8 and 9, the cartridgelid is configured with a beveled edge so that it remains secure in thehousing mounting area in use, which mounting area has matching bevelededges. FIGS. 8 and 9 also show rack mechanism 319 configured with sled317 to effectuate movement of a cartridge container 175 of cartridge 170slideably under the cartridge top to align the container under thecartridge top undersurface configured to have dispensing port(s) in aclosed inhaler configuration or cartridge dispensing or dosing positionor configuration when inhaler 302 is ready for dosing a user. In thedosing configuration, an air inlet port forms by the border of thecartridge top and the rim of the container, since the undersurface ofthe cartridge top is raised relative to the containment undersurface. Inthis configuration, an air conduit is defined through the cartridge bythe air inlet, the internal volume of the cartridge which is exposed toambient air and the openings in the cartridge top or dispensing port inthe cartridge top, which air conduit is in fluid communication with airconduit 340 of the mouthpiece.

Inhaler 302 can further include a mouthpiece cap 342 to protect the oralplacement portion of the mouthpiece. FIG. 8 depicts the inhaler of FIG.1 in cross-section through the mid-longitudinal axis with a cartridgeinstalled in the cartridge holder and in an open configuration, and inthe closed configuration FIG. 9 in a cartridge dispensing or dosingconfiguration.

FIG. 8 illustrates the position of cartridge 350 installed in holder ormounting area 315 and showing the internal compartment parts of inhaler302 and cartridge 170 relative to one another, including boss 326 withdispensing ports 327; gear mechanism 360, 363 and snaps 380 which assistin maintaining the device in a closed configuration.

FIGS. 10-16 illustrate yet another embodiment of the dry powder inhalerof the inhalation system. FIG. 10 depicts inhaler 900 in an openconfiguration which is structurally configured similarly as inhaler 302shown in FIGS. 1-9. Inhaler 900 comprises mouthpiece 930 and housingsubassembly 920 which are attached to one another by a hinge so thatmouthpiece 930 pivots relative to the housing subassembly 920.Mouthpiece 930 further comprises integrally formed side panels 932 widerthan housing 920, which engage with housing protrusions 905 to attainthe closed configuration of inhaler 900. Mouthpiece 930 furthercomprises air inlet 910, air outlet 935; air flow conduit 940 extendingfrom air inlet 910 to air outlet 935 for contacting a user's lips ormouth, and aperture 955 on the floor or bottom surface whichcommunicates with airflow conduit 940 of the inhaler. FIG. 12illustrates inhaler 900 in an exploded view, showing the component partsof the inhaler, including the mouthpiece 930 and housing subassembly920. As depicted in FIG. 12, the mouthpiece is configured as a singlecomponent and further comprises a bar, cylinder or tube 911 configuredwith teeth or gear 913 for articulating with housing 920 so thatmovement of mouthpiece 930 relative to housing 920 in an angulardirection attains closure of the device. An air channel 912 can beprovided to the housing which can direct an air flow towards mouthpieceair inlet 910. Air channel 912 is configured so that in use, a user'sfinger placed over the channel cannot limit or obstruct airflow into airconduit 940.

FIG. 12 illustrates the housing subassembly 920 comprising two partsmanufactured to make an enclosure and comprising a top portion having acartridge placement or mounting area 908 and a notch 918 which isconfigured to define an air inlet when the inhaler is in a closedconfiguration. FIG. 12 illustrates housing 920 as an enclosure, furthercomprising two component parts for ease of manufacturing, although lessor more parts can be used. The bottom portion of the housing forming hasno openings and includes a tray 922 and is connected to the top portionor cover 925 to form an enclosure or housing 920. Tray 922 is configuredwith notches 914 configured near its distal end which houses bar,cylinder or tube 911 in forming a hinge with mouthpiece 930. Tray 922also houses sled 917. Sled 917 is configured to be movable within tray922 and has a cartridge receiving area 921 and an arm-like structurehaving openings 915 for engaging the teeth or gear 913 of mouthpiece 930so that in closing the device for use, movement of mouthpiece 930relative to housing 920 moves the sled in a proximal direction, whichresults in the sled abutting a cartridge container seated on inhalerholder or mounting area 908 and can translocate the container from acontainment position to a dosing position. In this embodiment, acartridge seated in the cartridge holder 908 has the air inlet openingin a dosing configuration facing towards the proximal end of the inhaleror the user. Housing cover 925 is configured so that it can securelyattach to tray 922 by having, for example, protrusions 926 extendingfrom the bottom border as a securing mechanism. FIG. 12 illustratesinhaler 900 in the open configuration depicting the position andorientation of a cartridge 150 in a containment configuration to beinstalled in the mounting area of the inhaler. FIG. 13 furtherillustrates inhaler 900 in the open configuration with cartridge 150seated in the cartridge holder in the containment configuration. FIG. 14illustrates a mid-longitudinal section of the inhaler in FIG. 13 showingthe position of the gear 913 relative to sled 917 in the containmentconfiguration of the cartridge container 151, which abuts sled 917. Inthis embodiment, container 151 moves relative to cartridge top 156. Uponclosing inhaler 900 (FIG. 15) and as mouthpiece 930 moves to attain aclosed configuration, sled 917 pushes container 151 until the dosingconfiguration is attained and mouthpiece aperture 955 slides overcartridge boss 126 so that dispensing ports 127 are in communicationwith the mouthpiece conduit 940 and an air flow pathway is establishedfor dosing through air inlet aperture 918, cartridge air inlet 919 anddispensing ports 127 in air conduit 940. As seen in FIG. 16, mouthpiece930 and therefore, air conduit 940 have a relatively tapered, hour-glassshape configuration at approximately mid to distal end. In thisembodiment, sled 917 is configured so that when the inhaler is openafter use, the sled cannot reconfigure a cartridge to the containmentconfiguration. In some variations of this embodiment, it may be possibleor desirable to reconfigure the cartridge depending on the powdermedicament used.

In embodiments disclosed herein, inhaler apertures, for example, 355,955 can be provided with a seal, for example, crushed ribs, conformablesurfaces, gaskets, and o-rings to prevent air flow leakage into thesystem so that the airflow only travels through the cartridge. In otherembodiment, to effectuate the seal, the seal can be provided to thecartridge. The inhalers are also provided with one or more zones ofdeagglomeration, which are configured to minimize build-up of powder ordeposition. Deagglomeration zones are provided, for example, in thecartridge, including, in the container and the dispensing ports, and atone or more locations in the air conduit of the mouthpiece.

Cartridge embodiments for use with the inhalers are describe above, suchas cartridges 150, 170, illustrated, respectively, in FIGS. 10, 13, 14,16-21, and in FIGS. 7-9, 22-30. The present cartridges are configured toform an enclosure having at least two configurations and contain a drypowder medicament in a storage, tightly sealed or contained position. Inthis and other embodiments, the cartridge can be reconfigured within aninhaler from a powder containment position to an inhalation or dosingconfiguration.

In certain embodiments, the cartridge comprises a lid or top and acontainer having one or more apertures, a containment configuration anddosing configuration, an outer surface, an inner surface defining aninternal volume; and the containment configuration restrictscommunication to the internal volume and the dispensing configurationforms an air passage through the internal volume to allow an air flow toenter and exit the internal volume in a predetermined manner. Forexample, the cartridge container can be configured so that an airflowentering the cartridge air inlet is directed across the air outletswithin the internal volume to meter the medicament leaving the cartridgeso that rate of discharge of a powder is controlled; and wherein airflowin the cartridge can tumble substantially perpendicular to the airoutlet flow direction, mix and fluidize a powder in the internal volumeprior to exiting through dispensing apertures.

In one embodiment, the cartridge can be coded with one or moreindicators, including, label, etching, color, frostings, flanges,ridges, and the like. For example, if color is selected, color pigmentsof various types, which are compatible with plastics and pharmaceuticalformulations or that are pharmaceutically-acceptable, can beincorporated during manufacturing of the cartridge. In this and otherembodiments, the color can denote a specific active ingredient or dosestrength, for example, a green lid can be indicative of 6 units of anFDKP and insulin formulation. Pharmaceutically acceptable colors can begreen, blue, teal, poppy, violet, yellow, orange, etc.

FIG. 17 further illustrate cartridge 150 comprising top or lid 156 andcontainer 151 defining an interior space or volume. FIG. 18 furtherexemplifies the cartridge top 156 having opposing ends and comprisingrecess area 154 and boss 126 at opposing ends of a longitudinal axis X,and relatively rectangular set of panels 152 along the sides and in thelongitudinal axis X, which are integrally configured and attached to top156 at their ends. The border 158 of cartridge top 156 extendsdownwardly and is continuous with panels 152. Panels 152 extenddownwardly from either side of top 156 in the longitudinal axis X andare separated from the area of boss 126 and recess area 154 by alongitudinal space or slit 157. FIGS. 17-21 also show each panel 152further comprising a flange 153 structurally configured to engage withprojections or wings 166 of container 151, support container 151 andallow container 151 to be movable from a containment position underrecess area 154 to a dosing position under area of boss 126. Panels 152are structurally configured with a stop 132 at each end to preventcontainer 151 from moving beyond their end where they are attached toborder 158. In this embodiment, container 151 or lid 156 can be movable,for example, by translational movement upon top 156, or top 156 can bemovable relative to the container 151. In one embodiment, container 151can be movable by sliding on flanges 153 on lid 156 when lid or top 156is stationary, or lid 156 can be movable by sliding on a stationarycontainer 151 depending on the inhaler configuration. Border 158 nearthe boss 126 has a recess area which forms part of the perimeter ofinlet port 119 in the dosing configuration of the cartridge.

FIG. 19 illustrates a bottom view of cartridge 150 showing therelationship of the structures in a containment configuration, such ascontainer 151, dispensing ports 127, panels 152, flanges 153 and areaunder the boss 126 or undersurface 168 which is relatively hollow orrecessed. FIG. 20 illustrates a cross-section through themid-longitudinal axis X of cartridge 150 in a containment configurationand showing container 151 in tight contact with lid 156 at recess area154 and supported by flanges 153. The undersurface of the boss 126 ishollow and can be seen relatively at a higher position than the topborder of container 151. FIG. 21 illustrates cartridge 150 in a dosingconfiguration wherein the upper border of container 151 and panel 158under the area of boss 126 form an inlet port 119 which allows flowentry into the interior of cartridge 151.

In another embodiment, a translational cartridge 170 is illustrated inFIGS. 22-30, which is an alternate embodiment of cartridge 150 and canbe used with, for example, inhaler 302 depicted in FIGS. 1-9. FIG. 22depicts cartridge 170 comprising an enclosure comprising a top or lid172 and a container 175 defining an interior space, wherein thecartridge is shown in a containment configuration. In this cartridgeconfiguration, the cartridge top 172 is configured to form a seal withcontainer 175 and container or lid is movable relative to one another.Cartridge 170 can be configured from a containment position (FIGS. 22and 29) to a dosing position (FIGS. 24-28 and 30) and to a disposableposition (not shown), for example, in the middle of the cartridge, toindicate that the cartridge has been used. FIG. 22 also illustrates thevarious features of cartridge 170, wherein top 172 comprises side panels171 configured to partially cover the exterior of the container. Eachside panel 172 comprises a flange 177 at its lower edge which forms atrack to support wing-like structures of container 175, which allowsmovement of container 175 along the lower border of top 172. Thecartridge top 172 further comprises an exterior relatively flat surfaceat one end, a relatively rectangular boss 174 having an opening ordispensing port 173, and a concave or recess area configured internallyto maintain the contents of container 175 in a tight seal. In oneembodiment, the dispensing port can be configured to have various sizes,for example, the width and length of the opening can be from about 0.025cm to about 0.25 cm in width and from about 0.125 cm to about 0.65 cm inlength at its entry within the interior of the cartridge. In oneembodiment, the dispensing port entry measures approximately 0.06 cm inwidth to 0.3 cm in length. In certain embodiments, cartridge top 172 cancomprise various shapes which can include grasping surfaces, forexample, tabs 176, 179 and other configurations to orient the cartridgein the right orientation for proper placement in the holder, and asecuring mechanism, for example, a chamfered or beveled edge 180 toadapt securely to a corresponding inhaler. The flanges, externalgeometry of the boss, tabs, and various other shapes can constitutekeying surfaces that can indicate, facilitate, and/or necessitate properplacement of the cartridge in the inhaler. Additionally, thesestructures can be varied from one inhaler-cartridge pairing system toanother in order to correlate a particular medicament or dosage providedby the cartridge with a particular inhaler. In such manner, a cartridgeintended for an inhaler associated with a first medicament or dosage canbe prevented from being placed into or operated with a similar inhalerassociated with a second medicament or dosage.

FIG. 23 is a top view of exemplifying the general shape of a cartridgetop 172 with boss 174, dispensing port 173, recess area 178 and tabs 176and 179. FIG. 24 is a bottom view of cartridge 170 showing container 175in a dosing position being supported by its wing-like projections 182 byeach flange 177 from top 172. FIG. 25 depicts cartridge 170 in a dosingconfiguration further comprising an air inlet 181 formed by a notch onthe cartridge top 172 and the container 175 upper border. In thisconfiguration, air inlet 181 is in communication with the interior ofthe cartridge and forms and air conduit with dispensing port 173. Inuse, the cartridge air inlet 181 is configured to direct airflowentering the cartridge interior at the dispensing port 173. FIG. 26depicts the cartridge 170 from the opposite end of the dosingconfiguration or back view of FIG. 25.

FIG. 27 illustrates a side view of cartridge 150, showing therelationship of the structures in a dosing configuration, such ascontainer 175, boss 174, side panels 172, and tab 176. FIG. 28illustrates a cartridge 170 in a dosing configuration for use andcomprising a container 175 and a top 172 having a relatively rectangularair inlet 181 and a relatively rectangular dispensing port 173 piercingthrough a boss 174 which is relatively centrally located on thecartridge top 172 upper surface. Boss 174 is configured to fit into anaperture within a wall of a mouthpiece of an inhaler. FIGS. 29 and 30illustrate cross-sections through the mid-longitudinal axis X ofcartridge 170 in a containment configuration and dosing configuration,respectively, showing container 175 in contact with the lid 172undersurface of the recess area 178 and supported by flanges 177 whichform tracks for the container to slide from one position to another. Asshown in FIG. 29, in the containment configuration, container 175 formsa seal with the undersurface of the cartridge top 172 at recess area178. FIG. 30 depicts the cartridge 170 in the dosing configurationwherein the container is at opposing end of the recess area 181 and thecontainer 175 and cartridge top form an air inlet 181 which allowsambient air to enter cartridge 170 as well as to form an air conduitwith dispensing port 173 and the interior of container 175. In thisembodiment, the cartridge top undersurface wherein the dosing positionis attained is relatively flat and container 175 interior surface isconfigured to have somewhat of a U-shape. The boss 174 is configured toslightly protrude above the top surface of cartridge top 172.

In other embodiments of the cartridge, the cartridge can be adapted tothe dry powder inhalers which are suitable for use with an inhaler witha rotatable mechanism for moving the inhaler or cartridge from acontainment configuration to a dosing position, wherein the cartridgetop is movable relative to the container, or for moving the containerrelative to the top in achieving alignment of the dispensing ports withthe container to a dosing position, or moving either the container orthe top to the containment configuration.

In embodiments described herein, cartridges can be configured to delivera single unit, pre-metered dose of a dry powder medicament in variousamounts depending on the dry powder formulation used. Cartridge examplessuch as cartridge 150, 170 can be structurally configured to contain adose of, for example, from 0.1 mg to about 50 mg of a dry powderformulation. Thus the size and shape of the container can vary dependingon the size of the inhaler and the amount or mass of powder medicamentto be delivered. For example, the container can have a relativelycylindrical shape with two opposing sides relatively flat and having anapproximate distance between of from about 0.4 cm to about 2.0 cm. Tooptimize the inhaler performance, the height of the inside of thecartridge along the Y axis may vary depending on the amount of powderthat is intended to be contained within the chamber. For example, a fillof 5 mg to 15 mg of powder may optimally require a height of from about0.6 cm to about 1.2 cm.

In an embodiment, a medicament cartridge for a dry powder inhaler isinhaler is provided, comprising: an enclosure configured to hold amedicament; at least one inlet port to allow flow into the enclosure,and at least one dispensing port to allow flow out of the enclosure; theat least one inlet port is configured to direct at least a portion ofthe flow entering the at least one inlet port at the at least onedispensing port within the enclosure in response to a pressuredifferential. In one embodiment, the inhaler cartridge is formed from ahigh density polyethylene plastic. The cartridge has a container whichhas an internal surface defining an internal volume and comprising abottom and side walls contiguous with one another, and having one ormore openings. The can have a cup-like structure and has one openingwith a rim and it is formed by a cartridge top and a container bottomwhich are configurable to define one or more inlet ports and one or moredispensing ports. The cartridge top and container bottom areconfigurable to a containment position, and a dispensing or dosingposition.

In embodiments described herein, a dry powder inhaler and cartridge forman inhalation system which can be structurally configured to effectuatea tunable or modular airflow resistance, as the system can beeffectuated by varying the cross-sectional area at any section of itsairflow conduits. In one embodiment, the dry powder inhaler system canhave an airflow resistance value of from about 0.065 to about 0.200(√kPa)/liter per minute. In other embodiments, a check valve may beemployed to prevent air flow through the inhaler until a desiredpressure drop, such as 4 kPa has been achieved, at which point thedesired resistance reaches a value within the range given herewith.

In the embodiments disclosed herein, the dry powder inhaler system isconfigured to have a predetermined flow balance distribution in use,having a first flow pathway through the cartridge and second flowpathway through, for example, the mouthpiece air conduit. FIG. 31 andFIG. 32 depict a schematic representation of air conduits established bythe cartridge and inhaler structural configurations which direct thebalance of flow distribution. FIG. 31 depicts the general direction offlow within a cartridge in the dispensing or dosing position of a drypowder inhaler as shown by the arrows. FIG. 32 illustrates the movementof flow of an embodiment of a dry powder inhaler showing the flowpathways of the inhaler in the dosing position as indicated by thearrows.

The balance of mass flow within an inhaler is approximately 20% to 70%of the volume going through the cartridge flow pathway, and about 30% to90% through the beginning portion of the mouthpiece conduit. In thisembodiment, the airflow distribution through the cartridge mixes themedicament in a tumbling manner to fluidize or aerosolize the dry powdermedicament in the cartridge container. Airflow fluidizing the powderwithin the container then lifts the powder and gradually lets the powderparticles exit the cartridge container through the dispensing ports,then shear from the airflow entering the mouthpiece conduit convergeswith the airflow containing medicament emanating from the cartridgecontainer. Predetermined or metered exiting airflow from the cartridgeconverge with bypass airflow entering the air conduit of the mouthpieceto further dilute and deagglomerate the powder medicament prior toexiting the mouthpiece outlet port and entering the patient.

In yet another embodiment, an inhalation system for delivering a drypowder formulation to a patient is provided, comprising an inhalercomprising a container mounting area configured to receive a container,and a mouthpiece having at least two inlet apertures and at least oneexit aperture; wherein one inlet aperture of the at least two inletapertures is in fluid communication with the container area, and one ofthe at least two inlet apertures is in fluid communication with the atleast one exit aperture via a flow path configured to bypass thecontainer area to deliver the dry powder formulation to the patient;wherein the flow conduit configured to bypass the container areadelivers 30% to 90% of the total flow going through the inhaler duringan inhalation.

In another embodiment, an inhalation system for delivering a dry powderformulation to a patient is also provided, comprising a dry powderinhaler comprising a container region and a container; the dry powderinhaler and container combined are configured to have rigid flowconduits in a dosing configuration and a plurality of structural regionsthat provide a mechanism for powder deagglomeration of the inhalationsystem in use; wherein at least one of the plurality of mechanisms fordeagglomeration is an agglomerate size exclusion aperture in thecontainer region having a smallest dimension between 0.25 mm and 3 mm.The term “rigid flow conduits” denotes air conduits of the inhalationsystem that do not change in geometry after repeated use, i.e., theconduits remain the same or constant and are not variable from use touse, as opposed to systems which operate with puncturing mechanisms foruse with capsules and blisters which may exhibit variability in conduitconfiguration from capsule to capsule or blister to blister.

In an alternate embodiment, an inhalation system for delivering a drypowder formulation to a patient is provided, comprising a dry powderinhaler comprising a mouthpiece and a container; the dry powder inhalerand container combined are configured to have rigid flow conduits in adosing configuration and a plurality of structural regions that providea mechanism for powder deagglomeration of the inhalation system in use;wherein at least one of the plurality of mechanisms for deagglomerationis an air conduit configured in the mouthpiece which directs flow at anexit aperture in fluid communication with the container. In particularembodiments, the inhalation system includes a container furthercomprising a mechanisms for cohesive powder deagglomeration whichcomprises a cup-like structure configured to guide a flow entering thecontainer to rotate, re-circulating in the internal volume of thecup-like structure and lifting up a powder medicament so as to entrainthe powder agglomerates in the flow until the powder mass is smallenough prior to exiting the container. In this embodiment, the cup-likestructure has one or more radii configured to prevent flow stagnation.

In embodiments describe herein, the cartridge is structurally configuredhaving the inlet opening in close proximity to the dispensing ports in ahorizontal and vertical axis. For example, the proximity of the inlet tothe dispensing ports can be immediately next to the air inlet to aboutwithin one cartridge width, although this relationship can varydepending on the flow rate, the physical and chemical properties of thepowder. Because of this proximity, flow from the inlet crosses theopening to the dispensing ports within the cartridge creating a flowconfiguration that inhibits fluidized powder or powder entrained withinthe airflow, from exiting the cartridge. In this manner, during aninhalation maneuver, flow entering the cartridge container caneffectuate tumbling of the dry powder formulation in the cartridgecontainer, and fluidized powder approaching the exit or dispensing portsof a cartridge can be impeded by flow entering the inlet port of thecartridge, thereby, flow within the cartridge can be restricted fromexiting the cartridge container. Due to differences in inertia, density,velocity, charge interaction, position of the flow, only certainparticles can navigate the path needed to exit the dispensing ports.Particles that do not pass through the exit port must continue to tumbleuntil they possess the proper mass, charge, velocity or position. Thismechanism, in effect, can meter the amount of medicament leaving thecartridge and can contribute to deagglomeration of powder. To furtherhelp meter the exiting fluidized powder, the size and number ofdispensing ports can be varied. In one embodiment, two dispensing portsare used, configured to be circular in shape, each 0.10 cm in diameterand positioned near the inlet aperture about middle center line of thecontainer to about 0.2 cm from the centerline towards the air inletport. Other embodiments can, for example, have dispensing ports ofvarious shapes including rectangular wherein the cross-sectional area ofthe one or more dispensing ports ranges from 0.05 cm² to about 0.25 cm².In some embodiments, the sizes ranging of the dispensing ports can befrom about 0.05 cm to about 0.25 cm in diameter. Other shapes andcross-sectional areas can be employed as long as they are similar incross-sectional area to the values given herewith. Alternatively, formore cohesive powders larger cross sectional area of the dispensing portcan be provided. In certain embodiments, the cross sectional area of thedispensing port can be increased depending on the size of theagglomerates relative to the minimum opening dimension of the port orports so that the length relative to the width of the port remainslarge. In one embodiment, the intake aperture is wider in dimension thanthe width of the dispensing port or ports. In embodiments wherein theintake aperture is rectangular, the air inlet aperture comprises a widthranging from about 0.2 cm to about the maximal width of the cartridge.In one embodiment the height is about 0.15 cm, and width of about 0.40cm. In alternate embodiments, the container can have a height of fromabout 0.05 cm to about 0.40 cm. In particular embodiments, the containercan be from about 0.4 cm to about 1.2 cm in width, and from about 0.6 cmto about 1.2 cm in height. In an embodiment, the container comprise oneor more dispensing ports having and each of the ports can have adiameter between 0.012 cm to about 0.25 cm.

In particular inhalation systems, a cartridge for a dry powder inhaler,comprising a cartridge top and a container is provided, wherein thecartridge top is configured relatively flat and having one or moreopenings and one or more flanges having tracks configured to engage thecontainer; the container having an inner surface defining an internalvolume and is moveably attached to the tracks on the one or more flangeson the cartridge top and configurable to attain a containment positionand a dispensing or dosing position by moving along the tracks of theone or more flanges.

In another embodiment, the inhalation system comprises an enclosurehaving one or more exit ports configured to exclude a powder mass of adry powder composition having a smallest dimension greater than 0.5 mmand less than 3 mm. In one embodiment, a cartridge for a dry powderinhaler, comprising an enclosure having two or more rigid parts; thecartridge having one or more inlet ports and one or more dispensingports, wherein one or more inlet ports have a total cross-sectional areawhich is larger than the total cross-sectional area of the dispensingports, including wherein the total cross-sectional area of one or moredispensing ports ranges from 0.05 cm² to about 0.25 cm².

In one embodiment, a method for deagglomerating and dispersing a drypowder formulation for inhalation, comprising the steps of: generatingan airflow in a dry powder inhaler comprising a mouthpiece and acontainer having at least one inlet port and at least one dispensingport and containing a dry powder formulation; the container forming anair conduit between the at least one inlet port and the at least onedispensing port and the inlet port directs a portion of the airflowentering the container to the at least one dispensing port; allowingairflow to tumble powder within the container so as to lift and mix thedry powder medicament in the container to form an airflow medicamentmixture; and accelerating the airflow exiting the container through theat least one dispensing port. In this embodiment, the powder medicamentthat passes through the dispensing ports can immediately accelerate dueto reduction in cross-sectional area of the exit ports relative to theinlet port. This change in velocity may further deagglomerate thefluidized and aerosolized powder medicament during inhalation.Additionally, because of the inertia of the particles or groups ofparticles in the fluidized medicament, the velocity of the particlesleaving the dispensing ports is not the same. The faster moving air flowin the mouthpiece conduit imparts a drag or shear force on each particleor group of particles of the slower moving fluidized powder leaving theexit or dispensing port or ports, which can further deagglomerate themedicament.

The powder medicament that passes through the dispensing port or portsimmediately accelerates due to reduction in cross-sectional area of theexit or dispensing ports relative to the container, which are designedto be narrower in cross-sectional area than the air inlet of thecontainer. This change in velocity may further deagglomerate thefluidized powder medicament. Additionally, because of the inertia of theparticles or groups of particles in the fluidized medicament, thevelocity of the particles leaving the dispensing ports and the velocityof the flow passing the dispensing ports is not the same.

In embodiments described herein, powder exiting the dispensing ports canfurther accelerate, for example, by an imparted change in directionand/or velocity of the fluidized medicament. Directional change offluidized powder leaving the dispensing port and entering the mouthpiececonduit can occur at an angle of approximately 0° to about 180°, forexample approximately 90°, to the axis of the dispensing port. Change inflow velocity and direction may further deagglomerate the fluidizedpowder through the air conduits. The change in direction can beaccomplished through geometric configuration changes of the air flowconduit and/or by impeding the air flow exiting the dispensing portswith a secondary air flow entering the mouthpiece inlet. The fluidizedpowder in the mouthpiece conduit expands and decelerates as it entersthe oral placement portion of the mouthpiece prior to exiting due to across-sectional area increase in the conduit. Gas trapped withinagglomerates also expands and may help to break apart the individualparticles. This is a further deagglomeration mechanism of theembodiments described herein. Airflow containing medicament can enterthe patient's oral cavity and be delivered effectively, for example,into the pulmonary circulation.

Each of the deagglomeration mechanisms described herein and part of theinhalation system represent a multi-stage approach which maximizespowder deagglomeration. Maximal deagglomeration and delivery of powdercan be obtained by optimizing the effect of each individual mechanism,including, one or more acceleration/deceleration conduits, drag, orexpansion of gas trapped within the agglomerates, interactions of powderproperties with those of the inhaler components material properties,which are integral characteristics of the present inhaler system. In theembodiments described herein, the inhalers are provided with relativelyrigid air conduits or plumbing system to maximize deagglomeration ofpowder medicament so that there is consistency of the powder medicamentdischarge from the inhaler during repeated use. Since the presentinhalers are provided with conduits which are rigid or remain the sameand cannot be altered, variations in the air conduit architectureresulting from puncturing films or peeling films associated with priorart inhalers using blister packs are avoided.

In one embodiment, there is provided a method of deagglomerating apowder formulation in a dry powder inhalation system, comprising:providing the dry powder formulation in a container having an internalvolume to a dry powder inhaler; allowing a flow to enter the containerwhich is configured to direct a flow to lift, entrain and circulate thedry powder formulation until the powder formulation comprises powdermasses sufficiently small to pass through one or more dispensingapertures into a mouthpiece. In this embodiment, the method can furthercomprise the step of accelerating the powder masses entrained in theflow leaving the one or more dispensing apertures and entering themouthpiece.

In embodiments disclosed herein, a dry powder medicament is dispensedwith consistency from the inhaler in less than about 2 seconds. Thepresent inhaler system has a high resistance value of approximately0.065 to about 0.20 (√kPa)/liter per minute. Therefore, in theinhalation system comprising a cartridge, peak inhalation pressure dropsof between 2 and 20 kPa produce resultant peak flow rates of aboutthrough the system of between 7 and 70 L/min. In some embodiments, thepressure differential for the inhaler and cartridge system can be below2 kPa. These flow rates result in greater than 75% of the cartridgecontents dispensed in fill masses between 1 and 30 mg of powder orgreater amounts. In some embodiments, these performance characteristicsare achieved by end users within a single inhalation maneuver to producecartridge dispense percentage of greater than 90%. In other embodiments,these performance characteristics are achieved by end users within asingle inhalation maneuver to produce cartridge dispense percentage ofabout 100%. In certain embodiments, the inhaler and cartridge system areconfigured to provide a single dose by discharging powder from theinhaler as a continuous flow of powder delivered to a patient. In someembodiments, it may be possible to configure the inhalation system todeliver powder in use as one or more pulses of powder dischargedepending on the particle sizes. In one embodiment, an inhalation systemfor delivering a dry powder formulation to a patient's lungs isprovided, comprising a dry powder inhaler configured to have flowconduits with a total resistance to flow in a dosing configurationranging in value from about 0.065 to about 0.200 (√kPa)/liter perminute. In this and other embodiments, the total resistance to flow ofthe inhalation system is relatively constant across a pressuredifferential range of between 0.5 kPa and 7 kPa.

The structural configuration of the inhalation system allows thedeagglomeration mechanism to produce respirable fractions greater than50% and particles of less than 5.8 μm. The inhalers can dischargegreater than 85% of a powder medicament contained within a containerduring an inhalation maneuver. Generally, the inhalers herein depictedin FIG. 151 can discharge greater that 90% of the cartridge or containercontents in less than 3 seconds at pressure differentials between 2 and5 kPa with fill masses ranging up to 30 mg.

In another embodiment, the present systems have a lower limit ofperformance. This performance limit is assigned based on inhatation of adry powder as described herein where a median particular particle sizedistribution is attained. A graph of PIP versus AUC can be formed wherea triangular area exists where PIP values are physically impossible toattain for a device given the AUC values. However, an acceptable areacan be formed based on a horizontal and vertical lines representingpassing criteria. The inhalation systems described herein have a lowerlimit for acceptable performance of a PIP of about 2 kPa and an AUC ofat least about 1.0, 1.1 or 1.2 kPa*sec.

In other embodiments, a lower limit and an upper limit for AUC exist.For example, AUC can range from about 1.0 to about 15 kPa*sec, fromabout 1.0 to about 10 kPa*sec, form about 1.1 to about 15 kPa*sec, fromabout 1.2 to about 10 kPa*sec, from about 1.2 to about 15 kPa*sec, orfrom about 1.2 to about 10 kPa*sec.

In another embodiment, adequately de-agglomerated doses of a dry powdermedicament using a high resistance dry powder inhaler are accomplishedby providing a high resistance dry powder inhaler containing a dose ofthe dry powder medicament; inhaling from the inhaler with sufficientforce to reach a peak inspiratory pressure of at least 2 kPa within 2seconds; and generating an area under the curve in the first second(AUC_(0-1sec)) of a inspiratory pressure-time curve of at least about1.0, 1.1, or 1.2 kPa*second; wherein VMGD (×50) of the emitted powder isless than about 5 um. In some embodiments a patient exerts a peakinspiratory pressure in two (2) seconds (PIP2 seconds) of greater thanor equal to 2 kPa and less than or equal to 15 or 20 kPa. In anotherembodiment, the dry powder medicament includes microparticles with amedian particle size VMGD (×50) of the emitted powder particles is notgreater than 1.33 times the median particle size when the inhaler isused optimally. In this and other embodiments, optimal inhaler use by apatient is when a patient exerts a peak inspiratory pressure in two (2)seconds (PIP2 seconds) of about 6 kPa. Optimal use can also berecognized by achieving a flow rate of approximately 28.3 L per minute.Similarly optimal usage can be that reflecting standard test conditionsfor aerodynamic particle size testing as specified, for example, in USP<601>.

The high resistance dry powder inhaler, in some embodiments, comprises adose of a dry powder medicament is inhaled by the patient withsufficient force (or effort) to reach a peak inspiratory pressure of atleast 2 kPa within 2 seconds; and generating an area under the curve inthe first second (AUC_(0-1sec)) of a inspiratory pressure versus timecurve of at least about 1.0, 1.1 or 1.2 kPa*sec; wherein greater than75% of the dry powder dose is discharged or emitted from the inhaler aspowder particles. In some embodiments the VMGD of the emitted particlesis less than about 5 microns.

Adequately de-agglomerated doses of a dry powder medication using a highresistance dry powder inhaler can be achieved by providing a highresistance dry powder inhaler containing a dose of a dry powdermedicament; inhaling from the inhaler with sufficient force to reach apeak inspiratory pressure of at least 2 kPa within 2 seconds; andgenerating an area under the curve in the first second (AUC_(0-1sec)) ofa inspiratory pressure-time curve of at least about 1.0, 1.1, or 1.2kPa*second; where n VMGD (×50) of the emitted powder is less than about5 um. In another embodiment, the dry powder medicament includesmicroparticles with a median particle size VMGD (×50) of the emittedpowder particles is not greater than 1.33 times the median particle sizewhen the inhaler is used optimally.

While the present inhalers are primarily described as breath-powered, insome embodiments, the inhaler can be provided with a source forgenerating the pressure differential required to deagglomerate anddeliver a dry powder formulation. For example, an inhaler can be adaptedto a gas powered source, such as compressed gas stored energy source,such as from a nitrogen can, which can be provided at the air inletports. A spacer can be provided to capture the plume so that the patientcan inhale at a comfortable pace.

In embodiments described herewith, the inhaler can be provided as areusable inhaler or as a single use inhaler. In alternate embodiments, asimilar principle of deagglomeration can be adapted to multidoseinhalers, wherein the inhaler can comprise a plurality of, for example,cartridge like structures in a single tray and a single dose can bedialed as needed. In variations of this embodiment, the multidoseinhaler can be configured to provide enough doses, for example, for aday, a week or a month's supply of a medication. In the multidoseembodiments described herein, end-user convenience is optimized. Forexample, in prandial regimens, breakfast, lunch and dinner dosing isachieved with a system configured to provide dosing for a course of 7days in a single device. Additional end-user convenience is provided bya system configured with an indicator mechanism that indicates the dayand dosing, for example, day 3 (D3), lunchtime (L).

In one embodiment, the dry powder medicament may comprise, for example,a diketopiperazine and a pharmaceutically active ingredient. In thisembodiment, the pharmaceutically active ingredient or active agent canbe any type depending on the disease or condition to be treated. Inanother embodiment, the diketopiperazine can include, for example,symmetrical molecules and asymmetrical diketopiperazines having utilityto form particles, microparticles and the like, which can be used ascarrier systems for the delivery of active agents to a target site inthe body. The term ‘active agent’ is referred to herein as thetherapeutic agent, or molecule such as protein or peptide or biologicalmolecule, to be encapsulated, associated, joined, complexed or entrappedwithin or adsorbed onto the diketopiperazine formulation. Any form of anactive agent can be combined with a diketopiperazine. The drug deliverysystem can be used to deliver biologically active agents havingtherapeutic, prophylactic or diagnostic activities.

One class of drug delivery agents that has been used to producemicroparticles that overcome problems in the pharmaceutical arts such asdrug instability and/or poor absorption, are the 2,5-diketopiperazines.2,5-diketopiperazines are represented by the compound of the generalFormula 1 as shown below wherein the ring atoms E₁ and E₂ at positions 1and 4 are either O or N to create the substitution analogsdiketomorpholine and diketodioxane, respectively, and at least one ofthe side-chains R₁ and R₂ located at positions 3 and 6 respectivelycontains a carboxylic acid (carboxylate) group. Compounds according toFormula 1 include, without limitation, diketopiperazines,diketomorpholines and diketodioxanes and their substitution analogs.

As used herein, “a diketopiperazine” or “a DKP” includesdiketopiperazines and pharmaceutically acceptable salts, derivatives,analogs and modifications thereof falling within the scope of thegeneral Formula 1.

These 2,5 diketopiperazines have been shown to be useful in drugdelivery, particularly those bearing acidic R¹ and R² groups (see forexample U.S. Pat. No. 5,352,461 entitled “Self AssemblingDiketopiperazine Drug Delivery System;” U.S. Pat. No. 5,503,852 entitled“Method For Making Self-Assembling Diketopiperazine Drug DeliverySystem;” U.S. Pat. No. 6,071,497 entitled “Microparticles For LungDelivery Comprising Diketopiperazine;” and U.S. Pat. No. 6,331,318entitled “Carbon-Substituted Diketopiperazine Delivery System,” each ofwhich is incorporated herein by reference in its entirety for all thatit teaches regarding diketopiperazines and diketopiperazine-mediateddrug delivery). Diketopiperazines can be formed into drug adsorbingmicroparticles. This combination of a drug and a diketopiperazine canimpart improved drug stability and/or absorption characteristics. Thesemicroparticles can be administered by various routes of administration.As dry powders these microparticles can be delivered by inhalation tospecific areas of the respiratory system, including the lung.

The fumaryl diketopiperazine(3,6-bis(N-fumaryl-4-aminobutyl)-2,5-diketopiperazine; FDKP) is onepreferred diketopiperazine for pulmonary applications:

FDKP provides a beneficial microparticle matrix because it has lowsolubility in acid but is readily soluble at neutral or basic pH. Theseproperties allow FDKP to crystallize under acidic conditions and thecrystals self-assemble to form particles. The particles dissolve readilyunder physiological conditions where the pH is neutral. In oneembodiment, the microparticles disclosed herein are FDKP microparticlesloaded with an active agent such as insulin.

FDKP is a chiral molecule having trans and cis isomers with respect tothe arrangement of the substituents on the substituted carbons on thediketopiperazine ring. As described in US Patent Application PublicationNo. 2010/0317574, entitled “Diketopiperazine microparticles with definedisomer contents,” more robust aerodynamic performance and consistency ofparticle morphology can be obtained by confining the isomer content toabout 45-65% trans. Isomer ratio can be controlled in the synthesis andrecrystallization of the molecule. Exposure to base promotes ringepimerization leading to racemization, for example during the removal ofprotecting groups from the terminal carboxylate groups. Howeverincreasing methanol content of the solvent in this step leads toincreased trans isomer content. The trans isomer is less soluble thanthe cis isomers and control of temperature and solvent compositionduring recrystallization can be used to promote or reduce enrichment forthe trans isomer in this step.

Microparticles having a diameter of between about 0.5 and about 10microns can reach the lungs, successfully passing most of the naturalbarriers. A diameter of less than about 10 microns is required tonavigate the turn of the throat and a diameter of about 0.5 microns orgreater is required to avoid being exhaled. Diketopiperazinemicroparticles with a specific surface area (SSA) of between about 35and about 67 m²/g exhibit characteristics beneficial to delivery ofdrugs to the lungs such as improved aerodynamic performance and improveddrug adsorption.

As described in PCT Publication No. WO2010144789, entitled“Diketopiperazine microparticles with defined specific surface areas,”the size distribution and shape of FDKP crystals are affected by thebalance between the nucleation of new crystals and the growth ofexisting crystals. Both phenomena depend strongly on concentrations andsupersaturation in solution. The characteristic size of the FDKP crystalis an indication of the relative rates of nucleation and growth. Whennucleation dominates, many crystals are formed but they are relativelysmall because they all compete for the FDKP in solution. When growthdominates, there are fewer competing crystals and the characteristicsize of the crystals is larger.

Crystallization depends strongly on supersaturation which, in turn,depends strongly on the concentration of the components in the feedstreams. Higher supersaturation is associated with the formation of manysmall crystals; lower supersaturation produces fewer, larger crystals.In terms of supersaturation: 1) increasing the FDKP concentration raisesthe supersaturation; 2) increasing the concentration of ammonia shiftsthe system to higher pH, raises the equilibrium solubility and decreasesthe supersaturation; and 3) increasing the acetic acid concentrationincreases the supersaturation by shifting the endpoint to lower pH wherethe equilibrium solubility is lower. Decreasing the concentrations ofthese components induces the opposite effects.

Temperature affects FDKP microparticle formation through its effect onFDKP solubility and the kinetics of FDKP crystal nucleation and growth.At low temperatures, small crystals are formed with high specificsurface area. Suspensions of these particles exhibit high viscosityindicating strong inter-particle attractions. A temperature range ofabout 12° C. to about 26° C. produced particles with acceptable (orbetter) aerodynamic performance with various inhaler systems includinginhaler systems disclosed herein.

These present devices and systems are useful in the pulmonary deliveryfor powders with a wide range of characteristics. Embodiments of theinvention include systems comprising an inhaler, an integral orinstallable unit dose cartridge, and powder of defined characteristic(s)providing an improved or optimal range of performance. For example, thedevices constitute an efficient deagglomeration engine and thus caneffectively deliver cohesive powders. This is distinct from the coursepursued by many others who have sought to develop dry powder inhalationsystems based on free flowing or flow optimized particles (see forexample U.S. Pat. Nos. 5,997,848 and 7,399,528, US Patent ApplicationNo. 2006/0260777; and Ferrari et al. AAPS Pharm Sci Tech 2004; 5 (4)Article 60). Thus, embodiments include systems plus a cohesive powder.

Cohesiveness of a powder can be assessed according to its flowability orcorrelated with assessments of shape and irregularity such as rugosity.As discussed in the US Pharmacopeia USP 29, 2006 section 1174 fourtechniques commonly used in the pharmaceutical arts to assess powderflowability: angle of repose; compressibility (Carr's) index and Hausnerratio; flow through an orifice; and shear cell methods. For the lattertwo no general scales have been developed due to diversity ofmethodology. Flow through an orifice can be used to measure flow rate oralternatively to determine a critical diameter that allows flow.Pertinent variables are the shape and diameter of the orifice, thediameter and height of the powder bed, and the material the apparatus ismade of. Shear cell devices include cylindrical, annular, and planarvarieties and offer great degree of experimental control. For either ofthese two methods description of the equipment and methodology arecrucial, but despite the lack of general scales they are successfullyused to provide qualitative and relative characterizations of powderflowability.

Angle of repose is determined as the angle assumed by a cone-like pileof the material relative to a horizontal base upon which it has beenpoured. Hausner ratio is the unsettled volume divided by the tappedvolume (that is the volume after tapping produces no further change involume), or alternatively the tapped density divided by the bulkdensity. The compressibility index (CI) can be calculated from theHausner ratio (HR) asCI=100×(1−(1/HR)).

Despite some variation in experimental methods generally accepted scalesof flow properties have been published for angle of repose,compressibility index and Hausner ratio (Carr, R L, Chem. Eng. 1965,72:163-168).

Compressibility Flow Character Angle of Repose Hausner Ratio Index (%)Excellent 25-30° 1.00-1.11 ≦10 Good 31-35° 1.12-1.18 11-15 Fair 36-40°1.19-1.25 16-20 Passable 41-45° 1.26-1.34 21-25 Poor 46-55° 1.35-1.4526-31 Very Poor 56-65° 1.46-1.59 32-27 Very, Very Poor ≧66° ≧1.60 ≧38

The Conveyor Equipment Manufacturers Association (CEMA) code provides asomewhat different characterization of angle of repose.

Angle of repose Flowability ≦19° Very free flowing 20-29° Free flowing30-39° Average ≧40° Sluggish

Powders with a flow character according to the table above that isexcellent or good can be characterized in terms of cohesiveness as non-or minimally cohesive, and the powders with less flowability as cohesiveand further dividing them between moderately cohesive (corresponding tofair or passable flow character) and highly cohesive (corresponding toany degree of poor flow character). In assessing angle of repose by theCEMA scale powders with an angle of repose ≧30° can be consideredcohesive and those ≧40° highly cohesive. Powders in each of theseranges, or combinations thereof, constitute aspects of distinctembodiments of the invention.

Cohesiveness can also be correlated with rugosity, a measure of theirregularity of the particle surface. The rugosity is the ratio of theactual specific surface area of the particle to that for an equivalentsphere:

${Rugosity} = \frac{({SSA})_{particle}}{({SSA})_{sphere}}$

Methods for direct measurement of rugosity, such as air permeametry, arealso known in the art. Rugosity of 2 or greater has been associated withincreased cohesiveness. It should be kept in mind that particle sizealso affects flowability so that larger particles (for example on theorder of 100 microns) can have reasonable flowability despite somewhatelevated rugosity. However for particles useful for delivery into thedeep lung, such as those with primary particle diameters of 1-3 microns,even modestly elevated rugosity or 2-6 may be cohesive. Highly cohesivepowders can have rugosities ≧10 (see Example A below).

Many of the examples below involve the use of dry powders comprisingFDKP. The component microparticles are self-assembled aggregates ofcrystalline plates. Powders comprised of particles with plate-likesurfaces are known to have generally poor flowability, that is, they arecohesive. Indeed smooth spherical particles generally have the bestflowability, with flowability generally decreasing as the particlesbecome oblong, have sharp edges, become substantially two dimensionaland irregularly shaped, have irregular interlocking shapes, or arefibrous. While not wanting to be bound, it is the Applicants' presentunderstanding that the crystalline plates of the FDKP microparticles caninterleave and interlock contributing to the cohesiveness (the inverseof flowability) of bulk powders comprising them and additionally makingthe powder more difficult to deagglomerate than less cohesive powders.Moreover factors affecting the structure of the particles can haveeffects on aerodynamic performance. It has been observed that asspecific surface area of the particles increases past a threshold valuetheir aerodynamic performance, measured as respirable fraction, tends todecrease. Additionally FDKP has two chiral carbon atoms in thepiperazine ring, so that the N-fumaryl-4-aminobutyl arms can be in cisor trans configurations with respect to the plane of the ring. It hasbeen observed that as the trans-cis ratio of the FDKP used in making themicroparticles departs from an optimal range including the racemicmixture respirable fraction is decreased and at greater departures fromthe preferred range the morphology of the particles in SEM becomesvisibly different. Thus embodiments of the invention include systems ofthe device plus diketopiperazine powders with specific surface areaswithin preferred ranges, and the device plus FDKP powders with trans-cisisomer ratios within preferred ranges.

FDKP microparticles either unmodified or containing a drug, for exampleinsulin, constitute highly cohesive powders. FDKP microparticles havebeen measured to have a Hausner ratio of 1.8, a compressibility index of47%, and an angle of repose of 40°. Insulin loaded FDKP microparticles(TECHNOSPHERE® Insulin; TI; MannKind Corporation, Valencia, Calif.) havebeen measured to have a Hausner ratio of 1.57, a compressibility indexof 36%, and an angle of repose of 50°±3°. Additionally in criticalorifice testing it was estimated that to establish flow under gravity anorifice diameter on the order of 2 to 3 feet (60-90 cm) would be needed(assumes a bed height of 2.5 feet; increased pressure increased the sizeof the diameter needed). Under similar conditions a free flowing powderwould require an orifice diameter on the order of only 1-2 cm (Taylor,M. K. et al. AAPS Pharm Sci Tech 1, art. 18).

Accordingly, in one embodiment, the present inhalation system comprisesa dry powder inhaler and a container for deagglomerating cohesive powderis provided, comprising a cohesive dry powder having a Carr's indexranging from 16 to 50. In one embodiment, the dry powder formulationcomprises a diketopiperazine, including, FDKP and a peptide or proteinincluding an endocrine hormone such as insulin, GLP-1, parathyroidhormone, oxyntomodulin, and others as mentioned elsewhere in thisdisclosure.

Microparticles having a diameter of between about 0.5 and about 10microns can reach the lungs, successfully passing most of the naturalbarriers. A diameter of less than about 10 microns is required tonavigate the turn of the throat and a diameter of about 0.5 microns orgreater is required to avoid being exhaled. Embodiments disclosed hereinshow that microparticles with a SSA of between about 35 and about 67m²/g exhibit characteristics beneficial to delivery of drugs to thelungs such as improved aerodynamic performance and improved drugadsorption.

Disclosed herein are also FDKP microparticles having a specific transisomer ratio of about 45 to about 65%. In this embodiment, themicroparticles provide improved flyability.

In one embodiment, there is also provided a system for the delivery ofan inhalable dry powder comprising: a) a cohesive powder comprising amedicament, and b) an inhaler comprising an enclosure defining aninternal volume for containing a powder, the enclosure comprising a gasinlet and a gas outlet wherein the inlet and the outlet are positionedso that gas flowing into the internal volume through the inlet isdirected at the gas flowing toward the outlet. In an embodiment, thesystem is useful for deagglomerating a cohesive powder having a Carr'sindex of from 18 to 50. The system can also be useful for delivering apowder when the cohesive powder has an angle of repose from 30° to 55°.The cohesive powder can be characterized by a critical orifice dimensionof ≦3.2 feet for funnel flow or ≦2.4 feet for mass flow, a rugosity >2.Exemplary cohesive powder particles include particles comprising of FDKPcrystals wherein the ratio of FDKP isomers in the range of 50% to 65%trans:cis.

In another embodiment, the inhalation system can comprise an inhalercomprising a mouthpiece and upon applying a pressure drop of ≧2 kPaacross the inhaler to generate a plume of particles which is emittedfrom the mouthpiece wherein 50% of the emitted particles have a VMGD of≦10 micron, wherein 50% of the emitted particles have a VMGD of ≦8microns, or wherein 50% of the emitted particles have a VMGD of ≦4microns.

In yet another embodiment, a system for the delivery of an inhalable drypowder comprising: a) a dry powder comprising particles composed of FDKPcrystals wherein the ratio of FDKP isomers in the range of 50% to 65%trans:cis, and a medicament; and b) an inhaler comprising a powdercontaining enclosure, the chamber comprising a gas inlet and a gasoutlet; and a housing in which to mount the chamber and defining twoflow pathways, a first flow pathway allowing gas to enter the gas inletof the chamber, a second flow pathway allowing gas to bypass the chambergas inlet; wherein flow bypassing the enclosure gas inlet is directed toimpinge upon the flow exiting the enclosure substantially perpendicularto the gas outlet flow direction.

In certain embodiments, a system for the delivery of an inhalable drypowder is provided, comprising: a) a dry powder comprising particlescomposed of FDKP crystals wherein the microparticles have a SSA ofbetween about 35 and about 67 m²/g which exhibit characteristicsbeneficial to delivery of drugs to the lungs such as improvedaerodynamic performance and improved drug adsorption per milligram, anda medicament; and b) an inhaler comprising a powder containingenclosure, wherein the enclosure comprises a gas inlet and a gas outlet;and a housing in which to mount the chamber and defining two flowpathways, a first flow pathway allowing gas to enter the gas inlet ofthe chamber, a second flow pathway allowing gas to bypass the chambergas inlet; wherein flow bypassing the chamber gas inlet is directed toimpinge upon the flow exiting the enclosure substantially perpendicularto the gas outlet flow direction.

A system for the delivery of an inhalable dry powder is also provided,comprising: a) a dry powder comprising a medicament, and b) an inhalercomprising a powder containing cartridge, the cartridge comprising a gasinlet and a gas outlet, and a housing in which to mount the cartridgeand defining two flow pathways, a first flow pathway allowing gas toenter the gas inlet of the cartridge, a second flow pathway allowing gasto bypass the enclosure gas inlet, and a mouthpiece and upon applying apressure drop of ≧2 kPa across the inhaler plume of particles is emittedfrom the mouthpiece wherein 50% of the emitted particles have a VMGD of≦10 microns, wherein flow bypassing the cartridge gas inlet is directedto impinge upon the flow exiting the enclosure substantiallyperpendicular to the gas outlet flow direction.

Active agents for use in the compositions and methods described hereincan include any pharmaceutical agent. These can include, for example,synthetic organic compounds, including, vasodialators, vasoconstrictormolecules, neurotransmitter analogs, neurotransmitter antagonists,steroids, anti-nociceptive agents, peptides and polypeptides,polysaccharides and other sugars, lipids, inorganic compound, andnucleic acid molecules, having therapeutic, prophylactic, or diagnosticactivities. Peptides, proteins, and polypeptides are all chains of aminoacids linked by peptide bonds.

Examples of active agents that can be delivered to a target or site inthe body using the diketopiperazine formulations, include hormones,anticoagulants, immunomodulating agents, vaccines, cytotoxic agents,antibiotics, vasoactive agents, neuroactive agents, anaesthetics orsedatives, steroid molecules such as glucocorticoids includingfluticasone, budesonide, mometasone, ciclesonide, flunisolide,betamethasone, and triamcinolone, decongestants, antivirals, antisense,antigens, and antibodies. More particularly, these compounds includeinsulin, heparin (including low molecular weight heparin), calcitonin,felbamate, sumatriptan, parathyroid hormone and active fragmentsthereof, growth hormone, erythropoietin, AZT, DDI, granulocytemacrophage colony stimulating factor (GM-CSF), lamotrigine, chorionicgonadotropin releasing factor, luteinizing releasing hormone,beta-galactosidase, exendin, vasoactive intestinal peptide, argatroban,small molecules, including anticancer and inhibitors or analogs of cellreceptors such as neurorecptors, including, anti-nociceptive agents;triptans including, Sumatriptan succinate, Almotriptan malate,Rizatriptan benzoate, Zolmitriptan, Eletriptan hydrobromide, Naratriptanhydrochloride, μ₂-agonists such as salbutamol fenoterol formoterolterbutaline pirbuterol, bitolterol, indacaterol, and the like, andvaccines. Antibodies and fragments thereof can include, in anon-limiting manner, anti-SSX-2₄₁₋₄₉ (synovial sarcoma, X breakpoint 2),anti-NY-ESO-1 (esophageal tumor associated antigen), anti-PRAME(preferentially expressed antigen of melanoma), anti-PSMA(prostate-specific membrane antigen), anti-Melan-A (melanoma tumorassociated antigen) and anti-tyrosinase (melanoma tumor associatedantigen).

In certain embodiments, a dry powder formulation for delivering apharmaceutical formulation to the pulmonary circulation comprises anactive ingredient or agent, including, a peptide, a protein, a hormone,analogs thereof or combinations thereof, wherein the active ingredientis insulin, calcitonin, growth hormone, erythropoietin, granulocytemacrophage colony stimulating factor (GM-CSF), chorionic gonadotropinreleasing factor, luteinizing releasing hormone, follicle stimulatinghormone (FSH), vasoactive intestinal peptide, parathyroid hormone(including black bear PTH), parathyroid hormone related protein,glucagon-like peptide-1 (GLP-1), exendin, oxyntomodulin, peptide YY,interleukin 2-inducible tyrosine kinase, Bruton's tyrosine kinase (BTK),inositol-requiring kinase 1 (IRE1), or analogs, active fragments,PC-DAC-modified derivatives, or O-glycosylated forms thereof. Inparticular embodiments, the pharmaceutical composition or dry powderformulation comprises fumaryl diketopiperazine and the active ingredientis one or more selected from insulin, parathyroid hormone 1-34, GLP-1,oxyntomodulin, peptide YY, heparin and analogs thereof; small molecules,including neurotransmitters, derivatives and/or analogs orinhibitors/antagonists, anti-nociceptive agents such as pain modulators,headache medications, anti-migraine drugs, including vasoactive agentssuch as triptans, and vaccine and adjuvants thereof; immunosuppressantmolecules and anticancer drugs.

In one embodiment, a method of self-administering a dry powderformulation to one's lung with a dry powder inhalation system is alsoprovided, comprising: obtaining a dry powder inhaler in a closedposition and having a mouthpiece; obtaining a cartridge comprising apre-metered dose of a dry powder formulation in a containmentconfiguration; opening the dry powder inhaler to install the cartridge;closing the inhaler to effectuate movement of the cartridge to a doseposition; placing the mouthpiece in one's mouth, and inhaling oncedeeply to deliver the dry powder formulation.

In one embodiment, a method of delivering an active ingredientcomprising: a) providing dry powder inhaler containing a cartridge witha dry powder formulation comprising a diketopiperazine and the activeagent; and b) delivering the active ingredient or agent to an individualin need of treatment. The dry powder inhaler system can deliver a drypowder formulation such as insulin FDKP having a respirable fractiongreater than 50% and particles sizes less than 5.8 μm.

In still yet a further embodiment, a method of treating obesity,hyperglycemia, insulin resistance, and/or diabetes is disclosed. Themethod comprises the administration of an inhalable dry powdercomposition or formulation comprising a diketopiperazine having theformula 2,5-diketo-3,6-di(4-X-aminobutyl)piperazine, wherein X isselected from the group consisting of succinyl, glutaryl, maleyl, andfumaryl. In this embodiment, the dry powder composition can comprise adiketopiperazine salt. In still yet another embodiment of the presentinvention, there is provided a dry powder composition or formulation,wherein the diketopiperazine is2,5-diketo-3,6-di-(4-fumaryl-aminobutyl)piperazine, with or without apharmaceutically acceptable carrier, or excipient.

In one embodiment, the inhalation system for delivering a dry powderformulation to a patient's lungs comprises a dry powder inhalerconfigured to have flow conduits with a total resistance to flow in adosing configuration ranging in value from 0.065 to about 0.200(√kPa)/liter per minute.

In one embodiment, a dry powder inhalation kit is provided comprising adry powder inhaler as described above, and one or more medicamentcartridge comprising a dry powder formulation for treating a disorder ordisease such as respiratory tract disease, diabetes and obesity. In thisembodiment, the kit can comprise materials with instructions for use.

The improved cartridge emptying and deagglomeration capabilities of theinhalation systems described herein contribute to increasedbioavailability of dry powder formulation. In particular embodiments,the dry powders are diketopiperazine containing powders. Bybioavailability we refer to the exposure to either the active ingredient(e.g. insulin) or the diketopiperazine (in those embodiments related todiketopiperazine powders) resultant from delivery into a subject'ssystemic circulation, as commonly assessed by the AUC of a concentrationversus time plot. By normalizing such measurements to dosage acharacteristic of the system can be revealed. The dosage used innormalizing exposure can be based on filled or emitted dose and can beexpressed in unit mass of powder. Alternatively exposure can benormalized to a cartridge of a particular fill mass. Either way exposurecan be further adjusted to take into account the specificdiketopiperazine or active ingredient content of a particularformulation, that is, the exposure can be normalized to the amount ofactive agent or the amount of diketopiperazine in the filled or emitteddose. Variables related to the subject, for example fluid volume, canaffect the observed exposure so in various embodiments bioavailabilityof the system will be expressed as a range or limit.

In one embodiment, the powder formulation can comprise microparticles ofFDKP and insulin as the active agent for the treatment of diabetes,wherein the insulin content of the formulation can be 3 U/mg, 4 U/mg, 6U/mg of powder or greater. The amount of insulin or dose to beadministered can vary depending on the patient's need. For example, inone embodiment, a single dose for a single inhalation can contain up toabout 60 U of insulin for the treatment of hyperglycemia in diabetes.

The pharmacokinetic profile of insulin is an important factor indetermining its physiologic effect. With similar insulin exposures aninsulin administration of a formulation which provides a pharmacokineticprofile characterized by a rapidly attained peak is more effective atsuppressing prandial glucose excursions and hepatic glucose release thanis an insulin administration resulting in a slower rise to C_(max) andcharacterized by an extended plateau. Thus, the inhalation systemsdisclosed herein also result in the more efficient delivery of insulinso that similar C_(max) levels can be attained with smaller doses ofinsulin as compared to prior art systems. Stated otherwise theseinhalations systems attain a higher dose normalized C_(max).

Example 1 Measuring the Resistance and Flow Distribution of a Dry PowderInhaler—Cartridge System

Several dry powder inhaler designs were tested to measure theirresistance to flow—an important characteristic determined in part by thegeometries or configurations of the inhaler pathways. Inhalersexhibiting high resistance require a greater pressure drop to yield thesame flow rate as lower resistance inhalers. Briefly, to measure theresistance of each inhaler and cartridge system, various flow rates areapplied to the inhaler and the resulting pressures across the inhalerare measured. These measurements can be achieved by utilizing a vacuumpump attached to the mouthpiece of the inhaler, to supply the pressuredrop, and a flow controller and pressure meter to change the flow andrecord the resulting pressure. According to the Bernoulli principle,when the square root of the pressure drop is plotted versus the flowrate, the resistance of the inhaler is the slope of the linear portionof the curve. In these experiments, the resistance of the inhalationsystem, comprising a dry powder inhaler and cartridge as describedherein, were measured in the dosing configuration using a resistancemeasuring device. The dosing configuration forms an air pathway throughthe inhaler air conduits and through the cartridge in the inhaler.

Since different inhaler designs exhibit different resistance values dueto slight variations in geometries of their air pathways, multipleexperiments were conducted to determine the ideal interval for pressuresettings to use with a particular design. Based on the Bernoulliprinciple of linearity between square root of pressure and flow rate,the intervals for assessing linearity were predetermined for the threeinhalers used after multiple tests so that the appropriate settingscould be used with other batches of the same inhaler design. Anexemplary graph for an inhaler can be seen in FIG. 33 for an inhalationsystem depicted in FIG. 7. The graph depicted in FIG. 33 indicates thatthe resistance of the inhalation system as depicted in FIG. 7 can bemeasured with good correlation to the Bernoulli principle at flow ratesranging from about 10 to 25 L/min. The graph also shows that theresistance of the exemplary inhalation system was determined to be 0.093√kPa/LPM. FIG. 33 illustrates that flow and pressure are related.Therefore, as the slope of the line in square root of pressure versusflow graph decreases, i.e., inhalation systems exhibiting lowerresistance, the change in flow for a given change in pressure isgreater. Accordingly, higher resistance inhalation systems would exhibitless variability in flow rates for given changes in pressure provided bythe patient with a breath powered system.

The data in Tables 1 show the results of a set of experiments using theinhalation system described in FIG. 10 (DPI 1), and FIG. 7 (DPI 2). Forthe dry powder inhaler 1 (DPI 1), the cartridge illustrated in design150, FIGS. 17-21, was used, and the cartridge illustrated in design 170,FIG. 22-30 was used with DPI 2. Accordingly, DPI 1 used Cartridge 1 andDPI 2 used Cartridge 2.

TABLE 1 Device Total Device % of Total Flow Tested Resistance CartridgeResistance Through Cartridge MEDTONE ® 0.1099 0.368 15.28 DPI 1 0.08740.296 29.50 DPI 2 0.0894 0.234 35.56

Table 1 illustrates the resistance of the inhalation system testedherewith is 0.0874 and 0.0894 √kPa/LPM, respectively for DPI 1 and DPI2. The data show that the resistance of the inhalation system to flow isin part determined by the geometry or configuration of the air conduitswithin the cartridge.

Example 2 Measurement of Particle Size Distribution Using an InhalerSystem with an Insulin Formulation

Measurements of the particle size distribution with a laser diffractionapparatus (Helos Laser Diffraction system, Sympatec Inc.) with anadaptor (MannKind Corp., U.S. patent application Ser. No. 12/727,179,which disclosure is incorporated herein by reference for its teaching ofthe relevant subject matter) were made of a formulation of variousamounts in milligram (mg) of an insulin and fumaryl diketopiperazineparticles provided in a cartridge-inhaler system as described herewith(inhaler of FIGS. 1-9 with cartridge 170 shown in FIGS. 22-30). Thedevice is attached at one end to tubing, which is adapted to a flowmeter (TSI, Inc. Model 4043) and a valve to regulate pressure or flowfrom a compressed air source. Once the laser system is activated and thelaser beam is ready to measure a plume, a pneumatic valve is actuated toallow the powder to be discharged from the inhaler. The laser systemmeasures the plume exiting the inhaler device automatically based onpredetermined measurement conditions. The laser diffraction system isoperated by software integrated with the apparatus and controlled bycomputer program. Measurements were made of samples containing differentamounts of powder and different powder lots. The measurement conditionsare as follows:

-   -   Laser measurement start trigger conditions: when ≧0.6% laser        intensity is detected on a particular detector channel;    -   Laser measurement end trigger conditions: when ≦0.4% laser        intensity is detected on a particular detector channel;    -   Distance between vacuum source and inhaler chamber is        approximately 9.525 cm.

Multiple tests were carried out using different amounts of powders orfill mass in the cartridges. Cartridges were only used once. Cartridgeweights were determined before and after powder discharge from theinhaler to determine discharged powder weights. Measurements in theapparatus were determined at various pressure drops and repeatedmultiple times as indicated in Table 2 below. Once the powder plume ismeasured, the data is analyzed and graphed. Table 2 depicts dataobtained from the experiments, wherein CE denotes cartridge emptying(powder discharged) and Q3 (50%) is the geometric diameter of the 50thpercentile of the cumulative powder particle size distribution of thesample, and q3(5.8 μm) denotes the percentage of the particle sizedistribution smaller than 5.8 μm geometric diameter.

TABLE 2 Pressure Fill Test Drop Discharge Mass Sample Q3 q3 No. (kPa)Time (s) (mg) Size % CE (50%) (5.8 μm) 1 4 3 6.7 30 98.0 4.020 63.8 2 43 6.7 20 97.0 3.700 67.4 3 4 3 6.7 20 98.4 3.935 64.6 4 4 3 3.5 20 97.84.400 61.0 5 2 4 6.7 7 92.9 4.364 61.0 6 2 4 6.7 7 95.1 4.680 57.9 7 4 46.7 7 97.0 3.973 64.4 8 4 4 6.7 7 95.5 4.250 61.7 9 6 4 6.7 7 97.3 3.83065.3 10 6 4 6.7 7 97.8 4.156 62.2

The data in Table 2 showed that 92.9% to 98.4% of the total powder fillmass was emitted from the inhalation system. Additionally, the dataindicate that regardless of the fill mass, 50% of the particles emittedfrom the inhalation system had a geometric diameter of less than 4.7 μmas measured at the various times and pressure drops tested. Moreover,between 60% and 70% of the particles emitted had a geometric diameter ofless than 5.8 μm.

FIG. 34 depicts data obtained from another experiment in which 10 mg ofpowder fill mass was used. The graph shows the particle sizedistribution of the sample containing particles of a formulationcomprising insulin and fumaryl diketopiperazine resulted in 78.35% ofthe measured particles had a particle size of ≦5.8 μm. The laserdetected 37.67% optical concentration during the measurement duration of0.484 seconds at the above measurement conditions. The data show thatthe inhalation system effectively deagglomerates the insulin-FDKPformulation to small sizes over a relevant and lower range of userinhalation capacities, i.e., pressure drops. These small geometric sizesfor this cohesive (Carr's index=36%) formulation are believed to berespirable.

Example 3 Measurement of Powder Discharge from a Cartridge as a Measureof Inhalation System Performance

The experiments were conducted using the inhalation system describedherewith using multiple inhaler prototypes depicted in FIGS. 1-9 withcartridge 170 prototypes as shown in FIGS. 22-30. Multiple cartridgeswere used with each inhaler. Each cartridge was weighed in an electronicbalance prior to fill. The cartridges were filled with a predeterminedmass of powder, again weighed and each filled cartridge was placed in aninhaler and tested for efficiency of emptying a powder formulation,i.e., TECHNOSPHERE® Insulin (insulin-FDKP; typically 3 U to 4 Uinsulin/mg powder, approximately 10-15% insulin w/w) powder batches.Multiple pressure drops were used to characterize the consistency ofperformance. Table 3 depicts results of this testing using 35 cartridgedischarge measurements per inhaler. In the data in Table 3, all testswere carried out using the same batch of a clinical grade insulin-FDKPpowder. The results show that relevant user pressure drops, ranging from2 through 5 kPa demonstrated a highly efficient emptying of the powderfrom the cartridge.

TABLE 3 Pressure Test Drop Discharge Fill Mass Sample Mean % CE No.(kPa) Time (s) (mg) Size % CE SD 1 5.00 3.00 3.08 35 99.42 0.75 2 5.003.00 3.00 35 98.11 1.11 3 5.00 3.00 6.49 35 99.49 0.81 4 5.00 3.00 6.5535 99.05 0.55 5 5.00 2.00 6.57 35 98.69 0.94 6 5.00 2.00 6.57 35 99.331.03 7 4.00 3.00 6.47 35 98.15 1.15 8 4.00 3.00 6.50 35 99.37 0.46 94.00 3.00 3.28 35 98.63 0.93 10 4.00 3.00 3.18 35 98.63 1.48 11 4.002.00 6.61 35 92.30 3.75 12 4.00 2.00 6.58 35 98.42 1.71 13 3.00 3.006.55 35 92.91 5.04 14 3.00 3.00 6.56 35 98.88 0.63 15 3.00 2.00 6.56 3596.47 3.19 16 3.00 2.00 6.59 35 99.49 0.54 17 3.00 1.00 6.93 35 98.062.37 18 3.00 1.00 6.95 35 98.74 0.67 19 3.00 1.00 3.12 35 97.00 1.06 203.00 1.00 3.15 35 96.98 0.99 21 2.00 1.00 6.53 35 97.24 1.65 22 2.001.00 6.49 35 98.48 2.27

Example 4 Measurement of Predictive Deposition by Andersen CascadeImpaction

The experiments were conducted using an Andersen Cascade Impactor tocollect stage plate powder deposits during a simulated dose deliveryusing flow rates of 28.3 LPM. This flow rate resulted in a pressure dropacross the inhalation system (DPI plus cartridge) of approximately 6kPa. Depositions on the plate stages were analyzed gravimetrically usingfilters and electronic balances. Fill weights of a cohesive powder in 10mg, 6.6 mg and 3.1 mg fill mass were evaluated for inhalation systemperformance. Each impaction test was conducted with five cartridges. Thecumulative powder mass collected on stages 2-F was measured inaccordance with aerodynamic particle sizes less than 5.8 μm. The ratioof the collected powder mass to the cartridge fill content wasdetermined and is provided as percent respirable fraction (RF) over thefill weight. The data is presented in Table 4.

The data show that a respirable fraction ranging from 50% to 70% wasachieved with multiple powder batches. This range represents anormalized performance characteristic of the inhalation system.

The inhaler system performance measurements were repeated 35 times witha different cartridge. Fill mass (mg) and discharge time (seconds) weremeasured for each inhaler cartridge system used. Additionally, thepercent of respirable fraction, i.e., particles suitable for pulmonarydelivery, in the powder was also measured. The results are presented inTable 4 below. In the table, the % RF/fill equals the percent ofparticles having a size (≦5.8 μm) that would travel to the lungs in thepowder; CE indicates cartridge emptying or powder delivered; RFindicates respirable fraction. In Table 4, Test Nos. 1-10 were conductedusing a second batch of a clinical grade of the insulin-FDKP powder, butthe test powder for 11-17 used the same powder as the tests conductedand presented in Table 3.

TABLE 4 Pressure Fill Drop Discharge Mass Sample Mean % RF/ % RF/ No.(kPa) Time (s) (mg) Size % CE Fill Delivered 1 6.4 8 9.7 5 98.9 56.658.3 2 6.4 8 9.9 5 88.8 53.7 60.4 3 6.4 8 8.2 5 97.5 54.9 56.9 4 6.4 86.7 5 98.4 56.8 58.1 5 6.4 8 10.0 5 89.2 60.4 67.8 6 6.4 8 9.6 5 99.353.5 53.9 7 6.4 8 9.6 5 98.2 57.3 58.4 8 6.4 8 9.6 5 99.0 56.9 57.5 96.4 8 9.6 5 95.4 59.3 62.1 10 6.4 8 6.6 5 99.4 61.7 62.1 11 6.4 8 6.6 599.6 59.0 59.2 12 6.4 8 6.6 5 96.5 62.6 64.8 13 6.4 8 6.6 5 98.7 59.860.6 14 6.4 8 3.1 5 99.5 66.3 66.6 15 6.4 8 3.1 5 99.7 70.7 70.9 16 6.48 3.1 5 97.6 65.9 67.5 17 6.4 8 3.1 5 98.2 71.6 73.0

The data above show that the present inhalation system comprising a drypowder inhaler and a cartridge containing a cohesive powder, i.e.,TECHNOSPHERE® Insulin (FDKP particles comprising insulin) can dischargeeffectively almost all of the powder content, since greater than 85% andin most cases greater than 95% of the total powder content of acartridge at variable fill masses and pressure drops were obtained withconsistency and significant degree of emptying. The Andersen cascadeimpaction measurements indicated that greater than 50% of the particlesare in the respirable range wherein the particles are less than 5.8 μmand ranging from 53.5% to 73% of the total emitted powder.

Example 5 Rugosity of TECHNOSPHERE® Insulin (TI)

The rugosity is the ratio of the actual specific surface area of theparticle to that for an equivalent sphere. The specific surface area ofa sphere is:

${SSA}_{sphere} = {\frac{\pi\; d_{eff}^{2}}{\rho\frac{\pi}{6}d_{eff}^{3}} = \frac{6}{\rho\; d_{eff}}}$where d_(eff)=1.2 μm is the surface-weighted diameter of TI particlesfrom Sympatec/RODOS laser diffraction measurements.An average sphere with the same density as the TI particle matrix (1.4g/cm³) would therefore have an SSA of

${SSA}_{sphere} = {\frac{6}{\rho\; d_{eff}} = {{\frac{6}{\left( {1.4\frac{g}{{cm}^{3}}} \right)\left( {1.2 \times 10^{- 6}\mspace{14mu} m} \right)}\left( \frac{m^{3}}{10^{6}\mspace{14mu}{cm}^{3}} \right)} = {3.6\mspace{14mu} m^{2}\text{/}g}}}$

Thus for TI particles with specific surface area (SSA) of approximately40 m²/g

${Rugosity} = {\frac{({SSA})_{TI}}{({SSA})_{sphere}} = {\frac{40\mspace{14mu} m^{2}\text{/}g}{3.6\mspace{14mu} m^{2}\text{/}g} \approx 11.}}$

For similarly sized particles with specific surface area of 50 or 60m²/g the rugosity would be roughly 14 and 16 respectively.

Example 6 Geometric Particle Size Analysis of Emitted Formulations byVolumetric Median Geometric Diameter (VMGD) Characterization

Laser diffraction of dry powder formulations emitted from dry powderinhalers is a common methodology employed to characterize the level ofde-agglomeration subjected to a powder. The methodology indicates ameasure of geometric size rather than aerodynamic size as occurring inindustry standard impaction methodologies. Typically, the geometric sizeof the emitted powder includes a volumetric distribution characterizedby the median particle size, VMGD. Importantly, geometric sizes of theemitted particles are discerned with heightened resolution as comparedto the aerodynamic sizes provided by impaction methods. Smaller sizesare preferred and result in greater likelihood of individual particlesbeing delivered to the pulmonary tract. Thus, differences in inhalerde-agglomeration and ultimate performance can be easier to resolve withdiffraction. In these experiments, an inhaler as specified in Example 3and a predicate inhaler are tested with laser diffraction at pressuresanalogous to actual patient inspiratory capacities to determine theeffectiveness of the inhalation system to de-agglomerate powderformulations. Specifically, the formulations included cohesivediketopiperazine powders with an active insulin loaded ingredient andwithout. These powder formulations possessed characteristic surfaceareas, isomer ratios, and Carr's indices. Reported in Table 5 are a VMGDand an efficiency of the container emptying during the testing. FDKPpowders have an approximate Carr's index of 50 and TI powder has anapproximate Carr's index of 40.

TABLE 5 pressure Inhaler drop sample VMGD system powder % trans SSA(kPa) size % CE (micron) DPI 2 FDKP 56 55 4 15 92.5 6.800 MEDTONE ® FDKP56 55 4 30 89.5 21.200 DPI 2 FDKP + active 56 45 4 30 98.0 4.020 DPI 2FDKP + active 56 45 4 20 97.0 3.700 DPI 2 FDKP + active 56 45 4 20 98.43.935 DPI 2 FDKP + active 56 45 4 20 97.8 4.400 MEDTONE ® FDKP + active56 45 4 10 86.1 9.280 MEDTONE ® FDKP + active 56 45 4 10 92.3 10.676 DPI2 FDKP + active 56 45 2 7 92.9 4.364 DPI 2 FDKP + active 56 45 2 7 95.14.680 DPI 2 FDKP + active 56 45 4 7 97.0 3.973 DPI 2 FDKP + active 56 454 7 95.5 4.250 DPI 2 FDKP + active 56 56 4 10 99.6 6.254 DPI 2 FDKP +active 56 14 4 10 85.5 4.037 MEDTONE ® FDKP + active 56 56 4 20 89.712.045 MEDTONE ® FDKP + active 56 14 4 20 37.9 10.776 DPI 2 FDKP +active 54 50 4 10 97.1 4.417 DPI 2 FDKP + active 54 44 4 10 96.0 4.189DPI 2 FDKP + active 56 35 4 10 92.0 3.235 DPI 2 FDKP + active 50 34 4 1093.2 5.611 DPI 2 FDKP + active 66 33 4 10 79.0 4.678 DPI 2 FDKP + active45 42 4 10 93.2 5.610 DPI 2 FDKP + active 56 9 4 10 78.9 5.860

These data in Table 5 show an improvement in powder de-agglomerationover a predicate inhaler system as compared to the inhaler systemdescribed herein. Diketopiperazine formulations with surface areasranging from 14-56 m²/g demonstrated emptying efficiencies in excess of85% and VMGD less than 7 microns. Similarly, formulations possessing anisomer ratio ranging from 45-66% trans demonstrated improved performanceover the predicate device. Lastly, performance of the inhaler systemwith formulations characterized with Carr's indices of 40-50 were shownto be improved over the predicate device as well. In all cases, thereported VMGD values were below 7 microns.

Example 7 In Vitro Performance Improvement Realized in a Next GenerationDry Powder Delivery System

TECHNOSPHERE® formulations have been successfully delivered to patientswith MEDTONE® delivery system (MTDS, MannKind Corporation, Valencia,Calif.). This system includes dry powder formulations, pre-metered intosingle-use cartridges and inserted into a high resistance,breath-powered, re-usable MEDTONE® inhaler. An improved delivery system(DPI 2 as described in Example 1) has been developed as an alternativeto MTDS. In vitro powder performance for these systems was compared forvarious parameter of inhaler performance. For DPI 2 a single dischargeper cartridge was used as compared to two discharges per cartridge inthe MEDTONE® system.

Particle sizing by laser diffraction and quantification of emitted massas described above were used in these experiments. A laser diffractioninstrument (Sympatec HELOS) was adapted with a novel pressurized inhalerchamber to facilitate analysis of powder plumes. MTDS cartridges weredischarged twice per determination versus once with DPI 2. Theinhalation systems were used with peak pressures of 4 kPa to assesspowder-emptying percentage and volumetric median geometric diameter(VMGD) with TECHNOSPHERE® (FDKP inhalation powder) and TECHNOSPHERE®Insulin (FDKP-insulin inhalation powder) formulations.

The results of the experiments are shown in Table 6 and FIG. 35. Insummary, for DPI 2, powder-emptying percentages were 97.8%(FDKP-insulin, fill weight 3.5 mg; n=20), 96.8% (FDKP-insulin, fillweight 6.7 mg; n=20), and 92.6% (FDKP inhalation powder, fill weight10.0 mg; n=15); VMGDs (microns) were 4.37, 3.69, and 6.84, respectively.For MTDS, powder-emptying percentages were 89.9% (FDKP-insulin, fillweight 5.0 mg; n=30), 91.7% (FDKP-insulin, fill weight 10.0 mg; n=30),and 89.4% (FDKP inhalation powder, fill weight 10.0 mg; n=30); VMGDs(microns) were 10.56, 11.23, and 21.21, respectively.

FIG. 35 depicts graphic representations of data obtained from theaverage of all tests performed for each inhalation system. As seen inFIG. 35, the cumulative distribution of particle sizes is smaller forDPI 2 than with MEDTONE®. When compared to MEDTONE®, the DPI 2inhalation system produces a larger percentage of smaller particles.This is evidence of an improved deagglomeration mechanism provided inthe DPI 2 system. These data support clinical use of DPI 2 as a viableand improved alternative for delivering FDKP inhalation powderformulations. Percent emptying was improved with DPI 2, offering usersthe significant advantage of a single discharge per cartridge comparedwith two discharges with MTDS. Reductions in median geometric particlesize suggest increased powder de-agglomeration within DPI 2. Theclinical impact of this improved de-agglomeration must now be assessed.

TABLE 6 Ave. Ave. Ave. Number of VMGD Geometric % Cartridge InhalerSystem Cartridges (μm) SD (μm) Emptying DPI 2 (3.5 mg FDKP- 20 4.37 2.7497.8 insulin) DPI 2 (6.7 mg FDKP- 20 3.69 2.73 96.8 insulin) DPI 2 (10mg FDKP) 15 6.84 3.79 92.6 MEDTONE ® (5 mg 30 10.56 2.92 89.9FDKP-insulin) MEDTONE ® (10 mg 30 11.23 2.93 91.7 FDKP-insulin)MEDTONE ® (10 mg 30 21.21 2.94 89.4 FDKP)

Example 8 Improvement in Bioavailability of FDKP with an ExemplaryEmbodiment of the Inhalation System

To assess the safety and tolerability of various fill weights ofTECHNOSPHERE® Inhalation Powder (FDKP-inhalation powder) delivered byDPI 1, described in Example 1 above, measurements were made using theinhalation system, i.e., inhaler and cartridge containing various fillweights of a dry inhalation powder, a modified CQLQ, VAS, and peak flowsof the inhalation system. The MEDTONE® inhaler system was used forcomparison. Experiments were also conducted to collect data from thesystems in used in order to assess the effect of altering inhalationefforts and inhalation times on the pharmacokinetics (PK) of FDKPinhaled as FDKP-Inhalation Powder through the DPI 1 inhaler.

At the onset of the study, subjects were monitored and instructed topractice taking “short” and “long” inhalations with the inhalationsystem adapted with a pressure sensing device as disclosed in U.S.patent application Ser. No. 12/488,469, which can detect the presence ofa dose emitted from the device in use. During an inhalation maneuver,the patient was instructed to maintain a nominal pressure differentialof 4-6 kPa combined with a short inhalation of 3-4 seconds or a longinhalation of 6-7 seconds. To generate a “hard” inhalation, the subjectprovided a nominal inhalation time of about 6.5 seconds and a peakpressure of 7 kPa. Conversely, to generate an “easy” inhalation, thesubject provided a nominal inhalation time of about 6.5 seconds and apeak pressure of 5 kPa. Coupled with the inhalation monitoringapparatus, gravimetric assessment of the powder mass discharged from thecartridge was performed. This enabled a linkage between inhalationmaneuver during dosing, cartridge discharge mass and pharmacokineticprofile determinations for each subject.

The study was an open-label, crossover, 2-part study in healthyvolunteers. In Part 1, a three-way, 3-period crossover study of 10 and15 mg of FDKP inhalation powder was inhaled through the DPI 1 Inhalerand 10 mg through the MEDTONE® inhaler. Ten subjects were administered adose of FDKP-inhalation powder and safety and tolerability measurements(CQLQ, VAS, and peak flows) were taken. Blood samples from the subjectswere taken prior to dosing and at 5, 10, 15, 25, 30, 60, 120, 240 and360 minutes after dosing to assess the pharmacokinetics of FDPK witheach treatment.

In Part 2, after determining the tolerability of FDKP-inhalation powderin Part 1, mg were then used in Part 2. Part 2 was carried out as a2-part, 2-way crossover study for evaluating the effect of flow rate (15versus 30 LPM) and inhalation time (3 versus 6 seconds). For eachparameter tested (i.e., flow rate, and inhalation time), ten subjectswere crossed over for each parameter with 20 subjects total for all ofthe parameters. Pharmacokinetics of FDPK was assessed with eachtreatment from blood samples taken from the subjects. Measurements ofpulmonary parameters (FEV1) were performed before and after inhalationof FDKP-inhalation powder. The results from these experiments are shownin the Table 7 and FIGS. 36 and 37.

Representative data of the results of the experiments are shown in Table7 below which illustrates the mean AUC_(0-6 hr) for FDKP measured forthe subjects tested as well as the mean C_(max).

TABLE 7 Mean Mean AUC SD AUC Cmax SD Cmax Treatment (ng * min/mL) (ng *min/mL) (ng/mL) (ng/mL) DPI 1 10 mg 28523 7375 189 96 (n = 10) DPI 1 15mg 32031 17368 242 178 (n = 10) MEDTONE ® 15143 3720 95 30 10 mg (n =10)

FIG. 36 depicts an example of a subject's profile using DPI 1 with a 10mg dose of FDKP as monitored by the sensing device showing a practiceinhalation without powder of about 4 seconds and a dosing inhalation ofabout 1 second with a powder dose of FDKP. FIG. 36 also shows that thedischarge mass from the cartridge was gravimetrically measured as 10.47mg, which resulted in the subject having a FDKP systemic exposurecharacterized by an AUC_(0-6 hrs) equaling 31,433 ng*min/mL. Thenormalized AUC/mg of delivered FDKP powder was 3,003 ng*min/mL per mg.FIG. 37 shows the FDKP concentration in blood plasma monitored for 6hrs, which shows a C_(max) of about 270 ng/mL in about 10 min.

The DPI 1 inhalation system containing 10 mg of FDKP powder deliveredalmost twice FDKP into the blood as the MEDTONE® inhaler containing 10mg. The DPI 1 inhalation system containing 15 mg of FDKP-inhalationpowder on average did not deliver a dose proportional in exposure ascompared to DPI 1 system containing 10 mg of powder, due to severalindividuals not having good exposure to the powder, as seen in thesignificantly higher standard deviation. Variations of the data in Part1 of the experiments may be due to some subjects not using the inhalersin the proper position during dosing.

The DPI 1 10 mg dose results for longer, shorter, harder or easierinhalation data compared to the MEDTONE® inhaler system are listed inTable 8. The study was conducted in three parts as indicated in Table 8.Table 8 illustrates delivery of the FDKP into the pulmonary circulationmeasured as the mean AUC_(0-∞) of FDKP values obtained in theexperiments. The data is exemplary of the effectiveness and performanceof the DPI 1 inhalation system compared to the MEDTONE® inhaler systemand shows that DPI 1 was more effective at delivering the FDKP into thesystemic circulation, at about 30% better than the MEDTONE® inhaler,wherein the values for DPI 1 ranged from AUC_(0-∞) 2375 to 5277ng*min/mL per mg of FDKP emitted in the formulation. AUC_(0-∞) forMEDTONE® ranged from 1465 to 2403 ng*min/mL per mg of FDKP emitted inthe formulation after two inhalations.

TABLE 8 FDKP delivered via DPI 1 and MT in 3 part study Part 1 Part 2Part 3 Inhaler System DPI 1 MT DPI 1 DPI 1 DPI 1 DPI 1 cartridge fdkpcontent (mg) 10 10 10 10 10 10 inhalation technique nominal time andlong short hard easy inhalation effort inhalation inhalation inhalationinhalation time time effort effort number of plasma analyses 10 10 10 1010 10 AUC (0-inf) fdkp mean (ng * min/mL) 32575 17657 30488 31879 3932438465 SD 7331 4281 8469 4713 11928 13248 plus 1 SD 39906 21938 3895736592 51252 51713 minus 1 SD 25244 13376 22019 27166 27396 25217 AVGemitted mass powder (mg) 9.32 9.13 9.27 9.63 10.17 9.8 AUC fdkp per 27091465 2375 2821 2694 2573 emitted fdkp mass minus 1 SD AVG mean AUC 34951934 3289 3310 3867 3925 fdkp per emitted fdkp mass (ng * min/mL * mgfdkp) AUC fdkp per 4282 2403 4202 3800 5040 5277 emitted fdkp mass plus1 SD Cmax fdkp mean (ng/mL) 189 96 206 196 256 230 SD 96 30 88 86 95 99

FDKP 10 mg as delivered by the DPI 1 device is more efficient atdelivering FDKP as measured by FDKP plasma AUC by an almost 2-foldincrease over MEDTONE®. The delivery of FDKP is independent ofinhalation time and inhalation effort. The data show that DPI 1 has animproved bioavailability and efficiency over MEDTONE® as assessed byFDKP AUC and the effect of altering inhalation parameters on FDKP AUC.The Cmax for FDKP in this study was greater than about 100 ng/mL withDPI 1 (one inhalation) and a lesser value using MEDTONE® (twoinhalations), i.e., 96±30 ng/mL.

Example 9 Improvement in Bioavailability of FDKP and Insulin with anExemplary Inhalation System

This study was designed to assess the relative bioavailability ofvarious fill weights of TECHNOSPHERE® insulin inhalation powder(FDKP-insulin) delivered by a pulmonary inhalation delivery system (DPI2) compared with MEDTONE® inhaler, as determined by the pharmacokinetics(PK) of insulin and FDKP.

This was an open-label, crossover, PK (insulin and FDKP) study inhealthy volunteers. C-peptide corrections were used to determine therelative amounts of insulin delivered by inhalation versus insulin ofendogenous origin. Twenty four subjects (12 per arm) were administered adose of 6.7 mg and 7.3 mg of FDKP-insulin inhalation powder (20 U and 22U insulin, respectively and about 10% insulin w/w) using a DPI 2, and 10mg FDKP-insulin inhalation powder (30 U insulin) using MEDTONE®.Subsequently, 12 subjects were given 20 U using DPI 2, or 30 U viaMEDTONE® in a 3-way crossover arm of the study. Blood samples from thesubjects were taken prior to dosing and at 7, 15, 30, 60, 120, 240 and360 minutes after dosing to assess the pharmacokinetics of FDPK witheach treatment.

The data show that 20 U or 22 U insulin using DPI 2 delivered similarexposures of insulin and FDKP compared with 30 U of insulin administeredwith MEDTONE®. For insulin, results of plasma exposures (AUC_(0-2hr))were 3407±1460 uU×min/mL vs. 4,154±1,682 uU*min/mL for DPI 2 20 U andMEDTONE® 30 U, respectively, and 4,661±2,218 uU*min/mL vs. 3,957±1,519uU*min/mL for DPI 2 containing 22 U and MEDTONE® 30 U, respectively. Inthe 3-way crossover arm, plasma insulin exposures were 4,091±1,189uU*min/mL and 3,763±1,652 uU*min/mL for DPI 2 and MEDTONE®,respectively.

The results from the 3-way study also showed a reduction in T_(max) forinsulin from 20.8±18.7 minutes in MEDTONE® to 14.8±8.94 minutes in DPI 2(20 U) and to 13.6±4.3 minutes using the DPI 2 (22 U) system. In the3-way cross-over study, wherein 6.7 mg FDKP-insulin was delivered in DPI2 vs. 10.0 mg of FDKP-insulin powder delivered in MEDTONE®, FDKP plasmaexposures (AUC_(0-2hr)) normalized for delivered mass were 2,059ng*min/mL/mg (average of 16 subjects doses) for DPI 2 compared to 1,324ng*min/mL/mg for MEDTONE® (average of 17 subjects doses). In thisexemplary embodiment, the bioavailability studies were conducted withapproximately 10% insulin content in the powder formulation.Accordingly, higher bioavailabilities (not normalized for powdercontent) can be obtained by providing a higher concentration of theinsulin, and similar results can be accomplished with other activeingredients. Similarly, formulations containing higher contents of anactive ingredient would yield lower bioavailabilies of FDKP (notnormalized for powder content).

In summary, DPI 2 was more efficient at delivering insulin as measuredby insulin plasma exposures than MEDTONE®. DPI 2 system deliveredsimilar insulin exposures with 20 U of insulin as that of MEDTONE® with30 U of insulin.

Further results from the experiments above are presented in the tablesbelow. The study described in the immediately above example wascontinued in two additional parts. In the second part of this studysubjects were given a dose of 10 U of insulin in an FDKP dry powderformulation using DPI 2, or 15 U of insulin in FDKP using the MEDTONE®inhalation system. In the 3^(rd) part of this study, subjects were given20 U of insulin in FDKP formulation using DPI 2 or 30 U using MEDTONE®in a 3-way crossover. Insulin concentration in blood was measured andthe results were analyzed and evaluated.

The plasma insulin and FDKP exposures (AUC_(0-2 hr)) attained fromsubjects treated using DPI 2 20 U is similar to that obtained fromsubjects using the MEDTONE® Inhaler. The data are presented in Tables 9.The values presented were obtained from all of the dosing groups thatused DPI 2 with 20 U of insulin, part I and III, while the values forthe MEDTONE® Inhaler 30 U of insulin were obtained from parts I, Ia andIII. Lower than expected AUC plasma exposure of insulin for DPI 2 22 Uis most likely secondary to insufficient time points during the terminalelimination phase of insulin. It was recognized that some of the latertime points were not contributing to the calculation of AUC and with anamendment were moved up in the timing sequence which gave improvedresults for AUC_(last). This change in the insulin pharmacokinetic timepoints after the DPI 2 22 U insulin cohort was completed improved thesubsequent concentration time profiles. The lower doses of DPI 2 10 Uand MEDTONE® Inhaler 15 U were also similar. Insulin concentrations fromall individuals are plotted in FIG. 38. The FDKP exposure from DPI 2 20U and MEDTONE® Inhaler 30 U as well as the FDKP exposure for DPI 2 10 Uand MEDTONE® Inhaler 15 U both fell within bioequivalent criteria. Thereis a good correlation with FDKP exposure and insulin exposure. FDKPconcentrations from all individuals are plotted by dose group in FIG.39.

The data in Table 9 is representative of the inhaler system performancedisclosed herein and shows that the average plasma mean AUC_(0-inf)measured for subjects in the experiment ranged from 1,879 to 3,383ng*min/mL per mg of FDKP emitted with MEDTONE® with two inhalations andfor DPI 2 from 2,773 to 5124 ng*min/mL per mg of FDKP emitted in theformulation after a single inhalation. The data also show that theaverage mean AUC_(0-inf) for FDKP per mg of emitted FDKP mass in theformulation for all subjects was greater 3,500 or 3,568 ng*min/mL.

Plasma insulin average mean AUC_(0-2hr) in this study for DPI 2 rangedfrom about 96 to 315 μU*min/mL per unit of insulin in the powderformulation administered in a single inhalation, wherein the averagemean of insulin ranged from 168 to 216 μU*min/mL per unit of insulin inthe powder formulation administered in a single inhalation. TheAUC_(0-inf) (AUC_(0-∞)) values for MEDTONE ranged from about 76 to about239 μU*min/mL per unit of insulin in the powder formulation administeredin two inhalations. It has been previously noted that the firstinhalation with the MEDTONE® inhaler system provides less than half thetotal insulin emitted with two inhalations per cartridge typically used(data not shown), and the same characteristic is similarly exhibited forFDKP when used as a delivery agent in the formulation.

Post prandial glucose excursions were evaluated in each subject duringthe test meal used to establish the insulin C-Peptide relationship, aswell as during meal challenges after the administration of insulin withDPI 2 or MEDTONE®. Glucose excursions in each individual comparingbetween DPI 2 or MEDTONE® are displayed in FIG. 40. The doses used inthe study were not titrated to the individual, so the magnitude of theresponse varies from individual, but generally comparable glucoseexcursions were seen in each individual between the treatments with thetwo inhalers.

TABLE 9 FDKP and insulin Pharmacokinetic Parameters using FDKP-insulindry powder formulation. Part 1 Part 2 Part 3 Part 4 Inhaler System DPI 2MT DPI 2 MT DPI 2 MT DPI 2 MT cartridge content (units of insulin) 20 3022 30 10 15 20 30 number of plasma analyses 11 11 10 12 10 10 17 18 AUC(0-2 hr) insulin Mean (uU * min/mL) 3407 4154 4661 3957 2268 2175 40913763 SD 1460 1682 2218 1519 958 1123 1189 1652 Mean minus 1 SD 1947 24722443 2438 1310 1052 2902 2111 Mean plus 1 SD 4867 5836 6879 5476 32263298 5280 5415 AVG emitted powder mass (mg) 6.78 9.13 7.27 9.24 3.494.59 6.81 9.14 AVG emitted insulin content (U) 20.34 27.39 21.81 27.7210.47 13.77 20.43 27.42 Mean AUC per emitted 95.72 90.25 112.01 87.95125.12 76.40 142.05 76.99 insulin content minus 1 SD AVG mean insulinAUC 167.50 151.66 213.71 142.75 216.62 157.95 200.24 137.24 per emittedinsulin content (uU * min/mL * U) Mean AUC per emitted 239.28 213.07315.41 197.55 308.12 239.51 258.44 197.48 insulin content plus 1 SD Cmaxinsulin mean uU/mL 76 86 127 103 53 49 103 89 SD 29 22 38 36 17 26 32 35AUC (0-inf) fdkp mean (ng * min/mL) 23826 23472 29107 26732 11084 1130822462 19806 SD 6055 4019 4050 3932 2108 1332 4362 4524 AVG emitted masspowder (mg) 6.78 9.13 7.27 9.24 3.49 4.59 6.81 9.14 AVG fdkp emittedcontent (mg) 6.03 8.13 6.47 8.22 3.11 4.09 6.06 8.13 Mean minus 1 SD17771 19453 25057 22800 8976 9976 18100 15282 Mean plus 1 SD 29881 2749133157 30664 13192 12640 26824 24330 mean AUC fdkp per 2945 2394 38732773 2890 2442 2986 1879 emitted fdkp mass minus 1 SD AVG mean AUG fdkp3948 2889 4499 3251 3568 2768 3706 2435 per emitted fdkp mass (ng *min/mL * mg fdkp) mean AUC fdkp per 4952 3383 5124 3729 4247 3094 44262991 emitted fdkp mass plus 1 SD Cmax fdkp mean (ng/mL) 175 161 219 19493 96 204 179 SD 69 29 49 49 23 25 46 57

The bioavailability of the inhalers was also assessed as compared to thebioavailability of fumaryl diketopiperazine or FDKP administered byintravenous bolus using radiolabeled FDKP and measured as AUC AUC_(0-∞).The results of this study showed that for the MEDTONE® systembioavailability was calculated to be about 26% and 32% for 10 mg and 20mg, respectively of FDKP powder delivered. The bioavailable obtainedmeasured using DPI 1 in a model analysis to deliver 10 mg of FDK was 57%when compared to a 10 mg of FDKP administered by an IV bolus injection.A model analysis of the data obtained using FDKP-insulin formulation wasused to assess inhaler system performance or efficiency of powderdelivered as measured by AUC_(0-∞) for FDKP using DPI 2 and a singleinhalation of the powder. DPI 2 delivered 64% of the FDKP from a 6.7 mgof total fill into the systemic circulation as compared to 46% forMEDTONE® with two inhalations. For this FDKP-insulin formulation, theFDKP content was about 6 mg.

Example 10 Pharmacokinetic Parameters Based on C-Peptide CorrectedInsulin Concentration Values and Geometric Means

In an arm of the study conducted as described in Example 9, 46 healthynormal volunteers were studied using a Phase 1, open-label, randomized,crossover study protocol. The studies were conducted to evaluate thebioequivalence of FDKP-insulin formulation administered using DPI 2inhalers which require a single inhalation to deliver a dose containedin a cartridge, when compared to MEDTONE®, which requires twoinhalations per cartridge to deliver a dose. Additionally, theexperiments were conducted to evaluate whether a dose of FDKP-insulininhalation powder of two cartridges containing 10 U doses delivered aninsulin concentration to a subject would be bioequivalent to onecartridge containing 20 U dose of insulin using DPI 2 inhalers andFDKP-insulin formulation administered by oral inhalation. Subjects wereadministered FDKP-insulin by oral inhalation using DPI 2 or MEDTONE®.Subjects received a single dose of 20 U insulin, two 10 U doses ofinsulin using DPI 2 inhalers or 30 U of insulin using a MEDTONE®inhaler. Blood samples were collected from each individual treated atvarious times for a period of 2 hours. The samples were analyzed tomeasure the insulin concentration. Pharmacokinetic parameters for thestudy were based on C-peptide corrected insulin concentration values.The results obtained from the study are shown in Table 10 below.

TABLE 10 20 U DPI 2 vs. 30 U MEDTONE ® PK Parameter 30 U 20 U DPI 2 vs.30 U Statistics MEDTONE ® 20 U DPI 2 MEDTONE ® AUC_(0-120 min) (min ×4060.3 4294.5 Ratio 1.060 μU/ml) 0.981-1.145 90% CI Cmax (μU/ml) 97.4105.2 Ratio 1.082 90% CI 0.992-1.180 2 × 10 U DPI 2 vs. 20 U DPI 2 PKParameter 2 × 10 U DPI 2 vs. Statistics 2 × 10 U DPI 2 20 U DPI 2 20UDPI 2 AUC_(0-120 min) (min × 4136.5 4294.5 Ratio 0.957 μU/ml)0.886-1.035 90% CI Cmax (μU/ml) 98.3 105.2 Ratio 0.930 90% CI0.852-1.014

The data indicate that using 20 U of insulin administered by oralinhalation to individuals using an FDKP-insulin formulation with a DPI 2delivery system is bioequivalent statistically to administering 30 U ofthe same formulation using a MEDTONE® inhaler. The data also indicatethat administering two 10 U doses of an FDKP-insulin formulation by oralinhalation with DPI 2 inhaler yields similar systemic exposure ofinsulin when compared to a single 20 U dose of insulin of anFDKP-insulin formulation using the same inhaler type or DPI 2.Therefore, two 10 U of insulin doses of FDKP-insulin formulation yieldsbioequivalent insulin concentration in the systemic circulation as asingle 20 U dose of FDKP-insulin using the DPI 2 inhaler system andadministered by pulmonary inhalation. The bioavailability data alsoindicate that using DPI 2 to dose patients, at least as exemplified withan insulin/FDKP formulation, that dosing with this inhalation system thedosing appears to be linear and proportional for at least the insulinrages tested, or from a 10 U to 30 U range.

The results also indicate that the DPI 2 delivery system is about 33%more efficient in delivering the same dose of the formulation.Therefore, DPI 2 provides similar exposures of an insulin dose with adose reduction of 33% when compared to MEDTONE® inhaler.

Example 11 Characterization of Inhalation Profiles Using In VitroInhaler Performance Based Metrics

An inhalation system described herewith consisting of a dry powderinhaler (DPI 2) with a cartridge. The DPI 2 was adapted with a BLUHALE™apparatus as disclosed in U.S. patent application Ser. No. 12/488,469(US 2009/0314292, which disclosure is incorporated herein by referencefor all it teaches regarding inhalation maneuver and efforts andmeasurements thereof), which measures the pressure differentialgenerated in an inhaler for a period of time during and after aninhalation maneuver. FIG. 41 is an exemplary graphic profile of a DPI 2wherein the pressure drop across the inhaler was measured for a periodof 5 seconds during and after a single inhalation. Peak inspiratorypressure in 2 sec, or PIP (2), denotes the highest point on the curve orhighest pressure attained during the first two seconds after initiationof an inhalation. FIG. 41 shows that PIP (2) for the DPI 2 was about 5kPa and the area under the curve within 1 second, or AUC (1) was 3.7kPa*sec.

Example 12 Inhaler Performance Threshold Testing Based on Particle SizeDiameter Tests

DPI 2 type inhalers were used in these experiments. Individual inhalerswere loaded with a cartridge containing a dry powder formulationcomprising microparticles comprising insulin and FDKP to testperformance of the devices. The inhalers had been previously used tocollect profiles as exemplified in Example 11 above. After collectingthe inhalation profiles with BLUHALE™, the inhalers were adapted to aninhalation simulator as described in Patent Application No.PCT/US2010/055323, which disclosure is incorporated herein by referencefor all it teaches regarding inhalation maneuver and efforts andmeasurements thereof, to reproduce exemplary inhalation by a user. Theinhalation profiles using the simulator were then applied to dischargepowder from two inhalers into a laser diffraction apparatus as describedin Example 2 above to measure the particle size distribution. The laserdiffraction apparatus measures the volumetric median geometric diameter(VMGD). Values were considered acceptable if 50% of the particlesemitted were less than 4.88 μm in diameter, which was selected based on33% increase in the average of particle size for a DPI 2 used optimally.Two inhalers with powder doses were loaded into the laser diffractionapparatus and powder discharges or emissions were obtained with thevarious inhalations profiles, i.e., various PIP (2) and AUC (1) values.The test was repeated 5 times for each inhaler for a total of tenmeasurements and the data was analyzed and plotted FIG. 42 shows theresults of the experiments as a graph of PIP (2) versus AUC (1) for thetwo inhalers, in which each point on the graph represents the average of10 discharges. The cartridge emptying (or dry powder emitted) wasgreater than 87% during all discharges. The triangular inhalationboundary region of the graph represents the area on the graph where PIP(2) values are physically impossible to attain for a device given theAUC (1) values. Inhalation maneuvers that were deemed to have passingcriteria based on the above specifications and were above and to theright of the Gen 2 passing criteria lines in FIG. 42 had acceptableperformance. The data in FIG. 42 show that the lower limit foracceptable performance of the present devices is at PIP (2) of about 2kPa and AUC (1) at least about 1.2 kPa*sec. However in otherexperiments, acceptable performance has also been demonstrated at an AUC(1) of at least about 1.0 or at least about 1.1 kPa*sec.

The preceding disclosures are illustrative embodiments. It should beappreciated by those of skill in the art that the devices, techniquesand methods disclosed herein elucidate representative embodiments thatfunction well in the practice of the present disclosure. However, thoseof skill in the art should, in light of the present disclosure,appreciate that many changes can be made in the specific embodimentsthat are disclosed and still obtain a like or similar result withoutdeparting from the spirit and scope of the invention.

Unless otherwise indicated, all numbers expressing quantities ofingredients, properties such as molecular weight, reaction conditions,and so forth used in the specification and claims are to be understoodas being modified in all instances by the term “about.” Accordingly,unless indicated to the contrary, the numerical parameters set forth inthe following specification and attached claims are approximations thatmay vary depending upon the desired properties sought to be obtained bythe present invention. At the very least, and not as an attempt to limitthe application of the doctrine of equivalents to the scope of theclaims, each numerical parameter should at least be construed in lightof the number of reported significant digits and by applying ordinaryrounding techniques. Notwithstanding that the numerical ranges andparameters setting forth the broad scope of the invention areapproximations, the numerical values set forth in the specific examplesare reported as precisely as possible. Any numerical value, however,inherently contains certain errors necessarily resulting from thestandard deviation found in their respective testing measurements.

The terms “a” and “an” and “the” and similar referents used in thecontext of describing the invention (especially in the context of thefollowing claims) are to be construed to cover both the singular and theplural, unless otherwise indicated herein or clearly contradicted bycontext. Recitation of ranges of values herein is merely intended toserve as a shorthand method of referring individually to each separatevalue falling within the range. Unless otherwise indicated herein, eachindividual value is incorporated into the specification as if it wereindividually recited herein. All methods described herein can beperformed in any suitable order unless otherwise indicated herein orotherwise clearly contradicted by context. The use of any and allexamples, or exemplary language (e.g. “such as”) provided herein isintended merely to better illuminate the invention and does not pose alimitation on the scope of the invention otherwise claimed. No languagein the specification should be construed as indicating any non-claimedelement essential to the practice of the invention.

The use of the term “or” in the claims is used to mean “and/or” unlessexplicitly indicated to refer to alternatives only or the alternativesare mutually exclusive, although the disclosure supports a definitionthat refers to only alternatives and “and/or.”

Groupings of alternative elements or embodiments of the inventiondisclosed herein are not to be construed as limitations. Each groupmember may be referred to and claimed individually or in any combinationwith other members of the group or other elements found herein. It isanticipated that one or more members of a group may be included in, ordeleted from, a group for reasons of convenience and/or patentability.When any such inclusion or deletion occurs, the specification is hereindeemed to contain the group as modified thus fulfilling the writtendescription of all Markush groups used in the appended claims.

Preferred embodiments of this invention are described herein, includingthe best mode known to the inventors for carrying out the invention. Ofcourse, variations on those preferred embodiments will become apparentto those of ordinary skill in the art upon reading the foregoingdescription. The inventor expects those of ordinary skill in the art toemploy such variations as appropriate, and the inventors intend for theinvention to be practiced otherwise than specifically described herein.Accordingly, this invention includes all modifications and equivalentsof the subject matter recited in the claims appended hereto as permittedby applicable law. Moreover, any combination of the above-describedelements in all possible variations thereof is encompassed by theinvention unless otherwise indicated herein or otherwise clearlycontradicted by context.

Specific embodiments disclosed herein may be further limited in theclaims using consisting of or consisting essentially of language. Whenused in the claims, whether as filed or added per amendment, thetransition term “consisting of” excludes any element, step, oringredient not specified in the claims. The transition term “consistingessentially of” limits the scope of a claim to the specified materialsor steps and those that do not materially affect the basic and novelcharacteristic(s). Embodiments of the invention so claimed areinherently or expressly described and enabled herein.

Furthermore, numerous references have been made to patents and printedpublications throughout this specification. Each of the above citedreferences and printed publications are herein individually incorporatedby reference in their entirety.

Further, it is to be understood that the embodiments of the inventiondisclosed herein are illustrative of the principles of the presentinvention. Other modifications that may be employed are within the scopeof the invention. Thus, by way of example, but not of limitation,alternative configurations of the present invention may be utilized inaccordance with the teachings herein. Accordingly, the present inventionis not limited to that precisely as shown and described.

We claim:
 1. A dry powder inhaler comprising: a) a mouthpiece; b) ahousing comprising a cartridge-mounting area and a cartridge, thecartridge comprising a movable container having a dry powder, thecontainer configured to move with respect to the cartridge and thecartridge configured to form a flow path between one or more inlet portsand one or more dispensing ports within the housing; and c) at least onerigid air conduit; wherein the rigid air conduit is configured so thatthe dry powder inhaler emits greater than about 75% of the dry powderfrom the container oriented in the container housing as powder particlesin a single inhalation, and the powder particles emitted have avolumetric median geometric diameter of less than about 5 microns whenthe single inhalation through the mouthpiece generates a peakinspiratory pressure of about 2 kPa within two seconds.
 2. The drypowder inhaler of claim 1 having a resistance value to airflow rangingfrom about 0.065 (√kPa)/liter per minute to about 0.200 (√kPa)/liter perminute.
 3. The dry powder inhaler of claim 1, wherein the dry powder isa formulation for pulmonary delivery and comprises an amount from about1 mg to about 30 mg of the dry powder.
 4. The dry powder inhaler ofclaim 1, wherein the dry powder comprises a diketopiperazine or apharmaceutically acceptable salt thereof.
 5. The dry powder inhaler ofclaim 4, wherein the diketopiperazine is of the formula2,5-diketo-3,6-bis(N—X-4-aminobutyl)piperazine, wherein X is selectedfrom the group consisting of fumaryl, succinyl, maleyl, and glutaryl. 6.The dry powder inhaler of claim 5, wherein the diketopiperazine is


7. The dry powder inhaler of claim 1, wherein the dry powder comprises adrug or an active agent.
 8. The dry powder inhaler of claim 7, whereinthe active agent is an endocrine hormone.
 9. The dry powder inhaler ofclaim 1, wherein the dry powder comprises a peptide, a polypeptide, orfragments thereof, a small organic molecule or a nucleic acid molecule.10. The dry powder inhaler of claim 9, wherein said peptide is insulin,glucagon, glucagon-like peptide-1, parathyroid hormone, oxytocin,oxyntomodulin, peptide YY, an exendin, analogs thereof or fragmentsthereof.
 11. The dry powder inhaler of claim 9, wherein the smallorganic molecule is a vasodialator, a vasoconstrictor, aneurotransmitter agonist or a neurotransmitter antagonist.
 12. The drypowder inhaler of claim 1, wherein the single inhalation generates anarea under the curve (AUC) from a pressure versus time curve within onesecond of at least about 1.0, 1.1 or 1.2 kPa*sec.
 13. The dry powderinhaler of claim 1, wherein the container is integrated into thecontainer housing and filled with a dry powder.
 14. A method ofdelivering of a dry powder using a high resistance dry powder inhalercomprising: providing a dry powder inhaler with an airflow resistancevalue ranging from about 0.065 (√kPa)/liter per minute to about 0.200(√kPa)/liter per minute, and containing the dose of the dry powderwithin cartridge comprising a container configured to move with respectto the cartridge to form a flow path for the delivery of the dry powder;applying sufficient force to reach a peak inspiratory pressure of atleast 2 kPa within 2 seconds; and generating an area under the curve inthe first second (AUC0-1 sec) of a inspiratory pressure versus timecurve of at least about 1.0, 1.1 or 1.2 kPa*sec; wherein greater than75% of the dose of the dry powder is discharged or emitted from theinhaler as powder particles.
 15. The method of claim 14, wherein the drypowder is a formulation for pulmonary delivery and comprises an amountfrom about 1 mg to about 30 mg of the dry powder.
 16. The method ofclaim 15, wherein the dry powder comprises a diketopiperazine or apharmaceutically acceptable salt thereof.
 17. The method of claim 16,wherein the diketopiperazine is of the formula3,6-bis(N—X-4-aminobutyl)-2,5-diketopiperazine, wherein X is selectedfrom the group consisting of fumaryl, succinyl, maleyl, and glutaryl.18. The method of claim 17, wherein the diketopiperazine is


19. The method of claim 18, wherein the dry powder formulation comprisesfumaryl diketopiperazine microparticles which upon discharge from thedry powder inhaler are measured to have a volumetric median geometricdiameter (VMGD) ranging from about 2 μm to 8 μm and a geometric standarddeviation of less than 4 μm.
 20. The method of claim 14, wherein the drypowder formulation comprises a drug or an active agent selected from thegroup consisting of a small organic molecule, peptide, polypeptide, aprotein, or a nucleic acid molecule.
 21. The method of claim 20, whereinthe small organic molecule is a vasoactive agent, a neurotransmitteragonist, a neurotransmitter antagonist, or a steroid molecule.